Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:11]([C:3]1[CH:4]=[CH:5][CH:9]=[CH:10][C:2]=1[OH:1])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 4-hydroxy-3-nitrobenzoic acid (1a) (1 g, 5.46 mmol), HOBt (1 g 7.4 mmol), DIC (1,3-diisopropylcarbodiimide, 1 mL, 6.4 mmol), an amino PEGA resin (1 g, 0.40 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[OH:25][C@@H]1CCNC1>>[OH:25][C@@H:3]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:2]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C1NCCn2c1cc1cc(OCCCN3CCCCC3)ccc12
Product: O=C1NCCn2c1cc1cc(OCCCN3CC[C@@H](O)C3)ccc12
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 2, from 8-(3-chloro-propoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 2, intermediate) and (R)-3-hydroxypyrrolidine (commercially available), to give the desired product as colorless solid (22%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:31][NH:32][CH3:33]>C1COCC1>[C:27]([O:26][C@@H:20]([C:4]1[C:3]([CH2:2][N:32]([CH3:33])[CH3:31])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:28])([CH3:29])[CH3:30]
Reactant: CNC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CBr)cc2ccccc2c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CN(C)C)cc2ccccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(3-(bromomethyl)-1-(4-chlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate (12 mg, 0.0245 mmol) in THF (1 mL) was added dimethylamine (2 M in THF, 0.12 μL). The reaction mixture was stirred at room temperature for 1 h. Removal of the solvent in vacuo followed by purification of the residue by flash chromatography (silica gel, ethyl acetate/hexanes) provided 8 mg of the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H33ClNO3: 454.2. Found: 454.2, 456.1.
Reaction SMILES: O[C:2]1[C:3]2[S:11][CH:10]=[CH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[C:3]2[S:11][CH:10]=[CH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)c2sccc2n1
Product: Cc1nc(Cl)c2sccc2n1

Procedure:
A suspension of 4-hydroxy-2-methylthieno[3,2-d]pyrimidine (0.631 g, 3.8 mmol) in POCl3 (10 mL, 400 mmol) was refluxed for 4 h, concentrated in vacuo, treated with saturated NaHCO3 (20 mL), extracted with EtOAc (2×20 mL) and the combined extracts dried (MgSO4) and concentrated in vacuo to give the title compound (0.645 g, 92% as a pale yellow solid: mp 82-84° C.; IR νmax (Nujol)/cm−1 3073, 2925, 2855, 1566, 1515, 1460, 1378, 1344, 1307, 894 and 795; NMR δH (400 MHz, DMSO-d6) 3.41 (3H, s), 7.72 (1H, d, J 5.0 Hz) and 8.61 (1H, d, J 5.0 Hz).
Reaction SMILES: C([NH:3][CH:4]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)=O.S(=O)(=O)(O)O.[Cl-].[Na+]>C(OCC)(=O)C>[NH2:3][CH:4]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(CC(NC=O)c2cccnc2)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(CC(N)c2cccnc2)cc1
Temperature: 60 °C
Yield: 31.9 %

Procedure:
To 0.38 g of methyl 4-[2-formamido-2-(3-pyridyl)ethyl]phenylacetate in 10 ml of methanol-1,4 dioxane (1:1) in solution was added 5 ml of 4% sulfuric acid, and stirred under heating at 60° C. for one hour, which was then poured into saturated aqueous sodium chloride solution for extraction with ethyl acetate. The ethyl acetate phase obtained was washed in saturated aqueous sodium chloride solution and dried over magnesium sulfate, followed by distillation of the solvent, to produce 0.11 g of methyl 4-[2-amino-2-(3-pyridyl)ethyl]phenylacetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH2:18][S:19]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:12](=[O:13])[C:11]4[CH:14]=[C:15]([CH2:18][S:19]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=4[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=2)[CH:33]=[N:32]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1c2cc(CS(=O)(=O)NCc3ccccn3)ccc2ccc2ncc(Cl)cc12
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)NCc5ccccn5)cc4c(=O)c3c2)cn1
Temperature: 130 °C

Procedure:
1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(pyridin-2-ylmethyl)methanesulfonamide (31.0 g, 72.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (22.72 g, 109 mmol), potassium fluoride (13.96 g, 240 mmol), tri-t-butylphosphonium tetrafluoroborate (2.112 g, 7.28 mmol), and Pd2(dba)3 (3.33 g, 3.64 mmol) were placed in a flask under an atmosphere of argon. DMF (364 ml) was added and argon was bubbled through the solution for several minutes. The solution was then heated at 130° C. for 6 h. The mixture was then cooled to room temperature, aqueous sodium hydrogen carbonate (saturated, 2000 mL) was added and the mixture was extracted with ethyl acatate (10×500 mL). The combined organic fractions were dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA to afford the title compound as a pale yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 9.21 (d, 1H); 8.53 (d, 1H); 8.47 (m, 1H); 8.46 (m, 1H); 8.15 (d, 1H); 8.14 (s, 1H); 7.78 (m, 4H); 7.39 (m, 2H); 7.32 (d, 1H); 7.24 (m, 1H); 4.63 (s, 2H); 4.22 (d, 1H); 3.88 (s, 3H). LRMS (APCI) calculated for C25H21N5O3S [M+H]+, 472.1. found 472.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Brc1nccs1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Oc2nccs2)cc1
Temperature: 160 °C
Yield: 54.8 %

Procedure:
To a solution of 4-isopropoxyphenol (CAS #7495-77-4. 3 g, 19.7 mmole), at room temperature in DMSO (30 mL) was added in turn, 2-bromothiazole (3.23 g, 19.7 mmole) and potassium carbonate (5.44 g, 39.4 mmole), heated at 160° C. for 3 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and brine sequentially, dried over magnesium sulfate, filtered and concentrated. The residue was purified on Silica gel column using a gradient of 5 to 25% ethyl acetate in hexane and provided 2.54 g (55%) of the title compound as yellowish oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.22 (d, J=3.68 Hz, 1H) 7.15-7.21 (m, 2H) 6.86-6.95 (m, 2H) 6.76 (d, J=4.04 Hz, 1H) 4.43-4.60 (heptet, J=6.25 Hz, 1H) 1.34 (d, J=6.25 Hz, 6H). MS (ESI) m/z 236 (M+H)+.
Reaction SMILES: [NH4+].[Br-].[C:3]1([NH2:10])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:10]=[C:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccccc1N
Reactant: COc1ccc(C=O)cc1
Agent: [Br-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(Cn2c(-c3ccc(OC)cc3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
In a methanol (5 mL) solvent in the presence of NH4Br (362.3 mg, 3.70 mmol), a solution including 1,2-phenylenediamine (100 mg, 0.92 mmol) and p-anisaldehyde (0.11 mL, 0.82 mmol) was stirred at room temperature for 6 hours, and methanol was evaporated therefrom. The residual was distributed between ethyl acetate and water. An organic layer was dried by using MgSO4, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (3:1) to obtain a solid Compound 116.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][OH:11])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].Cl[C:15]1[C:23]2[C:22]3[CH:24]=[C:25]([C:28]#[N:29])[N:26]=[CH:27][C:21]=3[N:20](COCC[Si](C)(C)C)[C:19]=2[N:18]=[CH:17][CH:16]=1>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([C:3]1([CH2:10][O:11][C:15]2[C:23]3[C:22]4[CH:24]=[C:25]([C:28]#[N:29])[N:26]=[CH:27][C:21]=4[NH:20][C:19]=3[N:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: CCC1(CO)CCN(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC1(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CCN(C)CC1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4-ethyl-1-methylpiperidin-4-yl)methanol (223 mg, 1.4 mmol) in tetrahydrofuran (3.2 mL) was added sodium hydride as 60% dispersion in mineral oil (57 mg, 1.4 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (150 mg, 0.42 mmol) was added in one portion and the reaction mixture was stirred at this temperature for 10 minutes, and then heated at 40° C. for 4 hours. The mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-10% methanol in methylene chloride) to afford the title compound as a white foam, which was used in the next step without any further purification (152 mg, 76%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:48]1([CH:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:45][CH2:46][NH:47][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCC(c4ccccc4)c4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 3,3-diphenylpropylamine. Purification was performed using HPLC with a normal phase column by eluting with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1), m.p. 214° C.; MS [(+)ESI, m/z]: 644 [M+H]+
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([C:2]4[NH:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)[CH:11]=3)[CH2:18][CH2:19]2)=[O:24])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1

Procedure:
Synthesised as described in Method X-Step c starting from 1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-4-carboxylic acid (0.1 g, 0.28 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.06 g, 0.34 mmol). (72%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[C@H:9]1[C:15](=[O:17])[NH:26][CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[F:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CO[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The mixture of (2S,3R)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (60.0 mg, 0.245 mmol), (3-chloro-2-fluorophenyl)methanamine (0.034 mL, 0.269 mmol), HBTU (139 mg, 0.367 mmol) and DIPEA (0.085 mL, 0.489 mmol) in CH2Cl2 (5 mL) was stirred for 20 h at RT. The reaction mixture was then diluted with CH2Cl2, and the organics were washed subsequently with 0.1N aqueous HCl (3×), aqueous NaHCO3 solution (2×) and brine. The organic layers were dried (Phase separator), concentrated in vacuo and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm; flow: 40 mL/min; eluent: 5-100% CH3CN/H2O for 20 min, 100% CH3CN for 2 min, CH3CN and H2O containing 0.1% TFA) to afford the title compound as a white solid. MS (LC/MS): 387 [M+H]+, 331 [MH−tBu]+, 287 [MH−Boc]+; tR (HPLC conditions b): 4.26 min.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:8]2)=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:48][NH:49][OH:50]>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:49]([OH:50])[CH3:48])=[O:18])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CNO
Reactant: O=C(O)c1cc2c(COC3CCOCC3)cn(Cc3ccc(F)cc3)c2cn1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Product: CN(O)C(=O)c1cc2c(COC3CCOCC3)cn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared as in example 116, step 3, using 1-(4-fluorobenzyl)-3-[(tetrahydro-2H-pyran-4-yloxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid, 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methyl morpholine, and N-methyl hydroxylamine hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38-1.48 (m, 2H) 1.84-1.91 (m, 2H) 3.28-3.37 (m, J=10.74, 10.74, 2.78 Hz, 5H) 3.60 (ddd, J=8.84, 4.80, 4.55 Hz, 1H) 3.80 (ddd, J=11.49, 4.29, 4.17 Hz, 2H) 4.69 (s, 2H) 5.54 (s, 2H) 7.16 (t, J=8.97 Hz, 2H) 7.36 (dd, J=8.72, 5.43 Hz, 2H) 7.86 (s, 1H) 8.03 (s, 1H) 8.89 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>C(Cl)Cl>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:37])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[CH:20][CH:21]=3)[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 126 (150 mg, 0.346 mmol) in DCM (7 mL) was added isopropyl isocyanate (265 mg, 3.11 mmol) and the reaction mixture was heated to reflux for 8 hours. The mixture was cooled to RT and concentrated. Purification by column chromatography (EtOAc) afforded the title compound 128 which was further triturated with Et2O (90 mg, 50% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.50 (d, J=5.28 Hz, 1H), 8.49 (s, 1H), 7.93 (d, J=8.41 Hz, 2H), 7.70 (m, 1H), 7.63 (d, J=8.41 Hz, 2H), 7.35 (t, J=9.19 Hz, 1H), 7.11 (m, 1H), 6.60 (d, J=5.48 Hz, 1H), 6.15 (d, J=7.63 Hz, 1H), 3.74 (m, 1H), 3.59-3.40 (m, 4H), 1.88-1.79 (m, 4H), 1.09 (d, J=6.46 Hz, 6H). MS (m/z)=519.65 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:20]3[N:19]=[N:18][C:17]([Cl:16])=[CH:22][CH:21]=3)[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1ccc(CN2CCC(Nc3ccc(Cl)nn3)CC2)cc1
Temperature: 120 °C

Procedure:
A solution of 1-(4-chlorobenzyl)-piperidin-4-yl amine (1 g, 4.45 mmol) (prepared by a procedure similar to that described in WO2001098273), 3,6-dichloropyridazine (670 mg, 4.45 mmol) and sodium carbonate (940 mg, 8.90 mmol) in dimethylacetamide (5 ml) was heated at 120° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 40 minutes. After this period, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. Purification by reverse phase HPLC (conditions as previously described) gave E16 (228 mg, 15%). C16H18Cl2N4 requires 336; Found 337 (MH+). 1H NMR (360 MHz, CDCl3) δ1.52 (qd, J=11.5, 3.5 Hz, 2H), 2.08 (d, J=12.5 Hz, 2H), 2.16 (t, J=11.3 Hz, 2H), 2.82 (d, J=11.5 Hz, 2H), 3.48 (s, 2H), 3.77-3.87 (m, 1H), 4.55 (d, J=7.8 Hz, 1H), 6.59 (d, J=9.3 Hz, 1H), 7.14 (d, J=9.3 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 7.29 (d, J=7.7 Hz, 2H)
Reaction SMILES: [NH2:1][C:2]1[N:21]=[C:5]2[NH:6][C:7]([CH3:20])=[C:8]([C:18]#[N:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C(N(CC)CC)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH:9]2[N:4]3[N:3]=[C:2]([N:1]4[C:25](=[O:26])[C:24]5[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:22]4=[O:27])[N:21]=[C:5]3[NH:6][C:7]([CH3:20])=[C:8]2[C:18]#[N:19])=[CH:15][CH:14]=1)#[N:17]
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N)nc2N1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1
Reaction time: 1 h

Procedure:
Under argon, (rac)-2-amino-7-(4-cyanophenyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (15 g, 54.1 mmol) together with phthalic anhydride (11.22 g, 75.7 mmol, 1.4 eq.) was suspended in a mixture of toluene (500 ml) and pyridine (600 ml), triethylamine (1.51 ml, 10.8 mmol, 0.2 eq.) was added and the mixture was heated under reflux overnight. More pyridine (200 ml), phthalic anhydride (8 g, 54.0 mmol, 1.0 eq.) and triethylamine (1.51 ml, 10.8 mmol, 0.2 eq.) were then added, and the mixture was heated under reflux for another 12 h. The reaction mixture was then concentrated under reduced pressure and the residue was dried under high vacuum (12 h). Three times, the crude product was suspended in ethanol (100 ml), stirred for 1 h, filtered off, washed with pentane and dried under high vacuum. The product obtained was a light-beige solid (20 g), which was recrystallised from DMF/methanol. To this end, the solid was initially dissolved in hot DMF (250 ml, 150° C.) and the cold DMF solution was then slowly, with stirring, poured into methanol (1.3 liters), whereupon the product precipitated out. The precipitate was filtered off and dried under high vacuum. Reprecipitation from DMF/methanol gave 15.91 g (99% pure, 71.5% of theory) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:39]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][C:42]([N:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[C:20]3[N:19]=[C:18]([CH:36]([CH3:38])[CH3:37])[C:17]([CH:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[C:13]([O:15][CH3:16])=[O:14])=[C:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:25]=3[CH2:24]2)=[CH:41][CH:40]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1ccc(-c3ccccc3)cc1)CC2(C)C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
A mixture of Cu(OAc)2 (16.42 mg, 0.090 mmol) and pyridine (7 μl, 0.09 mmol) in CH2Cl2 (1 mL) was stirred for 5 min. Added to this were methyl 2-(tert-butoxy)-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol), 4-biphenylboronic acid (17.90 mg, 0.09 mmol) and 34 mg molecular sieves. After stirring uncovered for 18 h, the mixture was adsorbed directly onto silica gel and was purified by flash column chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-(6-([1,1′-biphenyl]-4-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (22.7 mg, 84% yield) as a colorless oil. LCMS (M+H) calcd for C38H44FN2O3: 595.33. found: 595.4. 19F NMR (500 MHz, Methanol d4) δ ppm: −113.055.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.[BH4-].[Na+].CO>O1CCCC1>[C:18]([O:17][C:15]([N:6]1[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 80.5 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (8.11 g) in tetrahydrofuran (49 ml) stirring under ice cooling, sodium borohydride (2.36 g) and methanol (20 ml) are added. The mixture is stirred at room temperature for 25 minutes and at 60° C. for 25 minutes. The mixture is cooled with ice and filtered. The filtrate is concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is recrystallized from petroleum ether-ether to give (2S, 4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (5.96 g). Colorless crystals. Yield: 80%. mp. 95° to 96° C.