Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][C:4]=2[CH:3]=[C:2]1[C:9]([O:11][CH3:12])=[O:10].[C:13](O)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:13]([N:7]1[CH2:8][C:4]2[CH:3]=[C:2]([C:9]([O:11][CH3:12])=[O:10])[S:1][C:5]=2[CH2:6]1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)O
Reactant: COC(=O)c1cc2c(s1)CNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cc2c(s1)CN(C(=O)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate (0.023 g, 0.127 mmol) and pivalic acid (0.014 g, 0.14 mmol) in methylene chloride (0.92 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.055 g, 0.146 mmol) and N-methylmorpholine (0.035 mL, 0.32 mmol) respectively. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with additional DCM (2 mL) and washed with saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional DCM (3 mL), and the combined organic layers were concentrated to afford an oily residue. LCMS (FA) ES+ 268.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([N:22]([CH3:24])[CH3:23])[CH:16]=1>CCOC(C)=O>[NH2:21][C:19]1[N:20]=[C:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:16]=[C:17]([N:22]([CH3:24])[CH3:23])[N:18]=1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Reactant: CN(C)c1cc(Cl)nc(N)n1
Solvent: CCOC(C)=O
Product: CN(C)c1cc(-c2cc(F)c(C=O)c(F)c2)nc(N)n1
Yield: 79.2 %

Procedure:
The title compound was prepared following the General Procedure A using: (3,5-difluoro-4-formylphenyl)boronic acid (2.37 g, 12.8 mmol) and 6-chloro-N4,N4-dimethyl-2,4-pyrimidinediamine (2.2 g, 12.8 mmol). The solid was dissolved in EtOAc and precipitated with hexanes. The resulting solid was collected via vacuum filtration to afford the title compound (2.82 g, 80%) as a yellow solid. LC-MS (ES) m/z=279 [M+H]+.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=3)[C@H:5]2[CH:9]([CH3:10])[CH3:11])[CH2:3][CH2:2]1
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC(C)[C@@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (215 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (189 mg) and lithium carbonate (163 mg), the title compound was obtained as a pale-brown solid (yield: 227 mg, yield: 67%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cn1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-bromo-3-pyridinol (10 g, Commercial eg Apollo Scientific Ltd.) in DMF (100 ml) was added potassium carbonate (17.8 g). The reaction mixture was stirred for 15 min at 25-30 C before cooling to 15° C. To this was added slowly benzyl bromide (7.5 ml) and this was stirred at 25-30° C. for 48 h. The reaction mixture was poured into cold water and the solid was collected by filtration to give the title compound, 14.5 g
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[CH:25]([CH2:29][CH3:30])[C:26](Br)=[O:27]>O>[CH2:29]([CH:25]1[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1)[CH3:30]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CCC(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1Oc2cc(C(=O)OC)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (9.80 g) in a mixed solvent of ethyl acetate (200 ml) and water (200 ml) were added sodium hydrogen carbonate (7.30 g) and 2-bromobutyryl bromide (13.70 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (500 ml), to the solution was added potassium carbonate (8.90 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (12.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[CH3:25][N:26](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:24]=[C:2]([C:25]#[N:26])[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][C:17]([CH3:23])=[N:18]1)([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2cc(C#N)ccc2OCC3)n(C(C)C)n1
Temperature: 150 °C

Procedure:
A microwave vial was charged with a solution of 10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.200 mg, 0.466 mmol) in 1.4 ml DMF. To this solution was added zinc cyanide (160 mg, 1.4 mmol). The reaction mixture was degassed by bubbling nitrogen through the stirred mixture via a syringe. After several minutes the syringe was removed and Bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (66 mg, 0.093 mmol) was added and the reaction vial was quickly sealed. The sealed vial was flash heated in a microwave at 150° C. for 30 minutes. The cooled reaction was diluted with EtOAc and the organic solution was washed with water×1, saline×1 and dried (Na2SO4) before concentration in vacuo. The crude residue was purified by preparative RP-HPLC to give 455. MS: (ESI+)=335.1
Reaction SMILES: [Li].[O:2]1[C@H:4]2[C:5](=[O:31])[CH:6]=[C:7]3[C@:28]([CH3:29])([C@@H:3]12)[C@@H:27]1[C@H:10]([C@H:11]2[C@:24]([CH3:30])([CH2:25][CH2:26]1)[C@@H:14]([C@H:15]([CH3:23])[CH2:16][CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]2)[CH:9]=[CH:8]3.C(O)C>[NH4+].O1CCCC1>[OH:2][C@@H:3]1[C@@:28]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][CH:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH2:6][C@@H:5]([OH:31])[CH2:4]1
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -75 °C
Yield: 63 %

Procedure:
First, 1.80 g (35 equivalent amount) of metal lithium was dissolved in 130 ml of liquid ammonium under a nitrogen atmosphere and to the solution 3.00 g of 1α, 2α-epoxycholesta-4,6-dien-3,24- dione dissolved in 150 ml of tetrahydrofuran was dropwise added for 90 minutes while maintaining the temperature of the reaction mixture at -75° C. Then 60 minutes later, the temperature of the reaction mixture was increased to -34° C. for about 30 minutes and to the mixture was dropwise added 40.3 g (120 equivalent amount) of ethanol. Stirring was continued until the lithium layer floating as a liquid layer on the reaction mixture disappeared. Next, after evaporating most of the ammonia from the reaction mixture at room temperature, the same procedure as described in Reference Example 1 was carried out to obtain 1α, 3β, 24-trihydroxycholest-5-ene at a yield of 63%.
Reaction SMILES: COC1C=CC(C(F)(F)F)=CC=1N.C1N=C[N:16]([C:19](N2C=NC=C2)=[O:20])C=1.[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29].O>C(Cl)Cl>[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH:41][C:19]([NH2:16])=[O:20])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: COc1ccc(C(F)(F)F)cc1N
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc(NC(N)=O)cc2)ccn1
Reaction time: 16 h

Procedure:
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2Cl2 (15 mL) at 0° C. is added CDI (0.13 g). The resulting solution is allowed to warm to room temp. over 1 h, is stirred at room temp. for 16 h, then is treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g) from Step 2. The resulting yellow solution is stirred at room temp. for 72 h, then is treated with H2O (125 mL). The resulting aqueous mixture is extracted with EtOAc (2×150 mL). The combined organics are washed with a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue is triturated (90% EtOAc/10% hexane). The resulting white solids are collected by filtration and washed with EtOAc. The filtrate is concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)-N)-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a light tan solid: TLC (100% EtOAc) Rf 0.62; 1H NMR (DMSO-d6) δ 2.76 (d, Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m/z 461 ((M+H)+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[OH:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:15]2[NH:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([O:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)[CH:7]=1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1

Procedure:
0.19 g (1.01 mmol) 4,6-dichloro-2-methoxypyrimidine, 0.18 g (1.04 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one and 0.15 g (1.09 mmol) potassium carbonate in 1.5 mL DMF were stirred for 2 h at RT. Then water was added and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(Cl)[N+:14]([O-])=O)[C:6]#[N:7])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:5]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:21])[NH:14][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(C#N)C1C=CC=CC1(Cl)[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12

Procedure:
The synthesis route used to prepare analogues Is described in Scheme 3. (2-ethoxycarbonylmethyl-phenyl)-acetic acid ethyl ester 2 (71%) was obtained by hydrolysis of 1,2-phenylenediacetonitrile 1 with concentrated H2SO4. Compound 2 with sodium ethoxide in ethanol gave compound 3 (61%), which further reacted with guanidine in the presence of potassium t-butoxide under 150° C. in a microwave reaction to give compound 4 (34%). To access target compounds, first, compound 4 was tried to turn the 4-oxo to 4-chloro, which traditionally Is adopted in synthesizing 4-anilino substituted analogues. However, because of the lower aromaticity of the ring, the chlorination did not run well under known reaction conditions, Compound 4 was decomposed when refluxed with POCl3. Thus, the 4-oxo was converted to 4-sulfonate, which is a good leaving group for SNI reaction. Compound 5 was obtained when treating compound 4 with the 4-nitrobenzenesulfonyl chloride (36%). The target compound 6 with different substitution on the phenyl ring was obtained when refluxing compound 5 with corresponding aniline for 12-18 h.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]([C:13]1[CH:14]=[C:15](I)[CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][N:19]=[C:18]2[NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.C1COCC1>[NH2:10][C:11]([C:13]1[CH:14]=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][N:19]=[C:18]2[NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c(C(N)=O)cc(I)cc23)C1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c(C(N)=O)cc(-c4ccccc4)cc23)C1
Reaction time: 0.33 h

Procedure:
Combined phenylboronic acid (16.18 mg; 0.13 mmol; 1.20 eq.), tert-butyl (3S)-3-{[8-(aminocarbonyl)-6-iodoquinazolin-4-yl]amino}piperidine-1-carboxylate (55.00 mg; 0.11 mmol; 1.00 eq.), and bis(tri-tert-butylphosphoranyl)palladium (5.67 mg; 0.01 mmol; 0.10 eq.) in a microwave tube. Then added THF (0.70 ml) followed by cesium carbonate (0.22 ml; 2.00 M; 0.44 mmol; 4.00 eq.). Heated reaction in the microwave at 130 deg C. for 20 minutes. LCMS: M+1=448 major peak (266 present). Concentrated reaction. Purified by silica gel chromatography (Biotage; 10 g column; 15 mL/min; 1-10% MeOH/CH2Cl2). Concentrated product to give an oil. LCMS: M+1=448 major peak.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH:10]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1cnn(C2CCC(=O)CC2)c1
Product: Cc1cnn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(4-methyl-pyrazol-1-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12](Br)Br)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CC(C)=[O:17]>O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(C)=O
Reactant: Brc1ccc(C(Br)Br)c2ncccc12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1ccc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-Bromo-8-(dibromomethyl)quinoline (75 g, 0.197 mol) in Acetone (400 ml), Water (100 ml) was added Silvernitrate (75 g) at 0° C. in lots for 10 min and this reaction mixture was stirred at RT for 6 h. The reaction completion was confirmed by TLC. After completion of reaction the reaction mixture was filtered and the filterate was extracted with MTBE (1000 ml). The organic layer was washed with 10% NaHCO3 solution water, brine and the organic layer was dried over sodium sulphate and concentrated to afford the title compound as off white solid (15 g, 32% yield). 1H NMR (DMSO-d6 400 MHz): δ 11.272-11.27 (s, 1H), 9.17-9.15 (dd, J=4.2, 5.8 Hz, 1H), 8.64-8.62 (dd, J=8.6, 10.3 Hz, 1H), 8.17-8.15 (d, J=7.84, 1H), 8.09-8.07 (d, J=7.88 Hz, 1H), 7.85-7.82 (dd, J=8.64, 12.84 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=O)[CH2:6][C:7]1[N:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[C:23]#[N:24])[CH3:2].[F:27][C:28]([F:37])([F:36])[C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.O>CC(O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8]([CH:9]=[CH:10][C:11]([C:13]3[C:18]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12]2)=[C:23]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([C:28]([F:36])([F:37])[F:27])=[CH:30][CH:31]=2)[N:24]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C

Procedure:
Dissolve 3-(5-cyano-3′-trifluoromethyl-[2,2′]bipyridinyl-6-yl)-2-oxo-propionic acid ethyl ester (70 mg, 0.193 mmol) and 4-trifluoromethyl aniline (31 mg, 0.193 mmol) in AcOH (1 mL). Heat the mixture at 100° C. for 1.5 hours. Cool the mixture in ice and add H2O (5 mL). Extract three times with EtOAC (3×10 mL). Combine the organic extracts and wash with 1 N NaOH (30 mL) and brine (30 mL). Dry the organic extract over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product using silica gel chromatography eluting with hexane/acetone (3:1) to yield the title compound. MS 507.15 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg][Cl:48].ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:48][C:11]1[C:12]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C@@H:19]4[CH2:23][CH2:24][CH2:25][C@@H:18]34)[N:14]([CH2:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]=2[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9][C:10]=1[C:34]#[N:35]
Reactant: CC1(C)CCCC(C)(C)N1[Mg]Cl
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. solution of 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.2, Step 3; 250 mg, 0.509 mmol) in THF (7 mL) was added 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (Aldrich, 1M in THF/toluene) (1.02 mL, 1.02 mmol). The resulting solution was stirred at −78° C. for 45 minutes, and then hexachloroethane (301 mg, 1.273 mmol) was added as a solid in one portion. The reaction was allowed to warm slowly to 10° C. over 2 hours and then quenched with saturated NH4Cl (10 mL). EtOAc (75 ml) was added, and the organic layer was washed with water and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column eluting with 0 to 50% EtOAc/DCM afforded 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C27H30Cl2N6O [M+H]+=525. found=525.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][C:34](=[O:35])[O:36][CH2:37][CH3:38])=[CH:14][CH:13]=2)=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NCc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.16 g) (Example 285) in tetrahydrofuran (2 mL) were added ethyl chloroformate (0.035 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give ethyl (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)methylcarbamate (0.13 g, 87%) as pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:13][C:10]2[S:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[N:12][CH:11]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(Cc2cnc(NC(=O)OC(C)(C)C)s2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60 %

Procedure:
To a single necked round bottom flask (5-Formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1 g, 4.38 mmol) was dissolved in 20 ml methanol. To it piperidine-4-carboxylic acid ethyl ester (2.02 ml, 13.15 mmol) and 4-drops of glacial acetic acid was added and reaction mixture was stirred at room temperature for 2.5 hr. To it sodium cyanoborohydride (550 mg, 8.76 mmol) was added in portions and stirred for 12 hrs. Methanol was removed under reduced pressure using rotavapour. The residue was taken in water (15 ml) and ethyl acetate (25 ml), layers were separated, and aq. layer was re-extracted with ethyl acetate (25 ml). The combined organic layer was washed with brine (25 ml) and dried over anhydrous sodium sulfate. Solvent was evaporated on rotavapour, to get the yellow solid product. The crude material was purified by silica-gel column chromatography, eluting with 30-50% ethyl acetate in hexane. (0.98 g, 60% yield).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[CH2:15]([N:19]([C:22]1[C:27]([CH3:28])=[C:26](Cl)[N:25]=[C:24]([CH3:30])[N:23]=1)[CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18]>CS(C)=O>[CH2:15]([N:19]([CH2:20][CH3:21])[C:22]1[N:23]=[C:24]([CH3:30])[N:25]=[C:26]([CH:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:12])[C:10]#[N:11])[C:27]=1[CH3:28])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1C
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc(C(C#N)c2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.1 %

Procedure:
A solution of mesitylacetonitrile (66 mg, 0.41 mmol) in 1 ml of DMSO was treated with NaH (60% in oil, 20 mg 0.50 mmol) and stirred at room temperature for 20 minutes, butyl-(6-chloro-2,5-dimethylpyrimidin-4-yl)-ethylamine (100 mg, 0.414 mmol) was added and the resulting mixture was heated at 130° C. for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 160 mg of brown oil. The oil was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 6.83 (s, 2H), 5.49 (s, 1H), 3.2-3.4 (m, 2H), 3.0-3.2 (m, 2H), 2.51 (s, 3H), 2.24 (s, 3H), 2.21 (s, 6H), 1.66 (s, 3H), 1.35-1.50 (m, 2H), 1.1-1.3 (m, 2H), 1.05 (t, 3H), 0.84 (t, 3H) ppm.