Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:25]12[CH:30]([NH:31][C:32](=[O:48])[O:33][CH2:34][CH:35]3[C:47]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:41]4[C:36]3=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:29]1[CH2:28][NH:27][CH2:26]2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:27]3[CH2:26][CH:25]4[CH:29]([CH:30]4[NH:31][C:32](=[O:48])[O:33][CH2:34][CH:35]4[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=5[C:42]5[C:47]4=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:28]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: O=C(NC1C2CNCC21)OCC1c2ccccc2-c2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1C2CN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)CC21)OCC1c2ccccc2-c2ccccc21
Temperature: -60 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (1.0 g, 1.0 eq.) was dissolved in DCM (50 mL) and cooled to −60° C. where (9H-fluoren-9-yl)methyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate (1.09 g, 1.2 eq.), T3P (50% in EtOAc) (2.02 mL, 1.2 eq.) and DIPEA (0.95 mL, 2 eq.) was added. The clear reaction mixture was stirred at −60° C. for 1 h, quenched with water, and extracted with DCM. The organic layer was dried over sodium sulphate, concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (2% Methanol in DCM) to yield (Z)-(9H-fluoren-9-yl)methyl (3-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.26 g, 69% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([CH3:23])[CH:9]=1)=[O:6].[NH3:25]>CO>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][C:10]=1[CH3:23]
Reactant: N
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(C)c1
Solvent: CO
Product: Cc1cc(NC(=O)CC(N)=O)ccc1OCc1cccc(F)c1
Yield: 60 %

Procedure:
Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-3-methyl-phenyl]-malonamic acid methyl ester and 7M ammonia in methanol. Yield=60%. Colorless solid. MS: m/e=317.0 (M++H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:24]=[CH:23][CH:22]=[C:20]([NH2:21])[CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
4-phenoxyphenyl boronic acid (0.148 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) in DME (2 mL) were combined in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.065 g in 54% yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[N:18][C:19]([O:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:14]3[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[N:18][C:19]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:35]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)=[O:42])[CH2:23][CH2:22]4)=[C:14]3[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5cccnc5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500 mL round-bottomed flask was placed Compound A6 (146 mg, 0.36 mmol) and triethylamine (300 μl). DMF (15 mL) was added to completely dissolve the solid material. Nicotinoyl chloride hydrochloride (96 mg, 0.54 mmol) was added to the solution and the mixture was stirred overnight under N2 at room temperature. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by preparative HPLC to give Compound A7. 1H NMR (CDCl3, 400 MHz) δ 2.06 (m, 2H), 2.22 (m, 2H), 3.09 (s, 3H), 3.55 (m, 1H), 3.79 (m, 2H), 4.15 (m, 1H), 5.76 (m, 1H), 7.86 (m, 1H), 8.11 (d, 2H), 8.28 (s, 1H), 8.33 (d, 1H), 8.61 (d, 2H), 8.68 (s, 1H), 8.84 (m, 1H), 8.92 (m, 1H). LCMS calculated for C23H22N6O4S 478.14, observed 479.1 (MH+)
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccc(C(F)(F)F)cc2)CO3)N1
Temperature: 85 °C
Yield: 53.8 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.03 g, 2.75 mmole) and 4-trifluoromethylbenzylamine (1.60 ml, 11.2 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 5% methanol/CH2Cl2 as eluant. The free base of the title compound (0.56 g, 54%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.06 g of the (S) enantiomer of the title compound as an off-white solid fumarate, m.p. 211-212° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:13]([CH:9]1[CH2:8][C:7]2[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[C:10]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1cccc2c1C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cccc(OC)c2C1=O
Yield: 28 %

Procedure:
A solution of 26.4 g of 7-methoxy-1-indanone, 33.6 ml of 3-buten-2-ol and 265 mg of p-toluenesulfonic acid in 33.6 ml of 2,2-dimethoxypropane and 265 ml of anhydrous toluene was boiled under reflux for 17 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 9.9 g (28%) of (RS)-2-(2-buten-1-yl)-7-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:25][CH:24]=1)#[N:22]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C#N)cc3)ccn2c1=O
Yield: 94.3 %

Procedure:
Methyl 8-(4-cyano-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (123 mg, 0.42 mmol) and 4-cyano-phenyl-boronic acid (132 mg, 0.90 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (142 mg, 94%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:19]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].IC>C1COCC1>[CH3:19][O:1][CH2:2][C@H:3]([N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC(C)C[C@H](CO)N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
(R)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (example 9c) (5.88 g, 23.87 mmol) was dissolved in dry THF (25 mL) and hexamethyl-phosphoramide (30 mL) and the solution cooled to 0° C. Sodium hydride (60% in mineral oil, 1.15 g, 28.65 mmol) was added and after 10 minutes iodomethane (7.43 ml, 119.35 mmol) was added dropwise and the solution was warmed up slowly to room temperature and stirred over night. The reaction mixture was poured into ice/water, extracted with EtOAC, washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (20% EtOAC in hexane) to give 3.92 g of (R)-2-(1-methoxy-4-methylpentan-2-yl)isoindoine-1,3-dione (63%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C(=O)(O)[O-].[Na+].[NH:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:16]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19].Cl>CN(C=O)C.O>[NH:15]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:16]([C:21]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CSCC[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
D-Met-OH (1.4 g, 10 mM) and sodium bicarbonate (1.68 g, 20 mM) were added to a mixture of water (15 ml) and DMF (5 ml). Boc-Leu-OSu (3.28 g, 10 mM) in DMF (30 ml) was added thereto and the mixture was stirred overnight at room temperature. After cooling to 0° C., the pH was adjusted to pH 6.5 with 1 N-HCl and the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate-1 N-HCl (50 ml-50 ml). The ethyl acetate layer was washed with water, dried by adding sodium sulfate and ethyl acetate was distilled off. The residue was charged on a column of silica gel (100 g) and eluted with benzene-ethyl acetate (1:1) to obtain Boc-Leu-D-Met-OH (1.6 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:7][CH2:8][CH2:9][C:10]#[N:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: N#CCCCc1ccccc1
Product: N#CCCCc1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
4-Phenylbutyronitrile (12.7 g) was added dropwise to stirred concentrated nitric acid (55 ml) at 5°-10° C. and the mixture was stirred for 2 hours at 20°-25° C. The deep yellow solution was poured onto ice and extracted with dichloromethane. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:4) to isolate the minor product.
Reaction SMILES: [OH-].[K+:2].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:17]#[C:18]C(C)CO)[CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)=[O:6]>C(O)CCC>[C:17]([C:9]1[CH:10]=[C:11]([C:13]([O-:15])=[O:14])[CH:12]=[C:7]([CH:8]=1)[C:5]([O-:6])=[O:4])#[CH:18].[K+:2].[K+:2]
Reactant: COC(=O)c1cc(C#CC(C)CO)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: C#Cc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Yield: 97 %

Procedure:
Into a 5 liter four-necked flask equipped with a thermometer, a Dimroth condenser and a stirrer, 3 liters of n-butanol and 182 g (2.763 moles) of potassium hydroxide (85%) were placed and dissolved by heating under the refluxing condition. To the obtained solution, 95 g (0.344 moles) of 4-(3,5-bis(methoxycarbonyl)phenyl)-2-methyl-3-butyn-1-ol synthesized above was added and the resultant mixture was heated for 30 minutes under the refluxing condition. The reaction mixture was then cooled in an ice bath and the formed crystals were separated by filtration. The crystals were washed twice with 1 liter of ethanol and dried at 60° C. under a reduced pressure and 88.87 g of dipotassium 5-ethynyl-isophthalate was obtained (the yield: 97%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
A solution of [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (compound 1.1; 1.0 mmol, prepared according to the procedure of Hah, J. M. et. al J. Med. Chem 46, 2003, 1661) and triethylamine (“TEA”; 3.0 equivalents) in anhydrous tetrahydrofuran (“THF”; 5.0 mL) is treated with the dropwise addition of benzoyl chloride (1.1 equivalents) at 0° C. After completion of the reaction, the mixture is partitioned between water and diethyl ether. The organic layer is separated, washed with 1.0 N HCl, saturated sodium bicarbonate, brine and dried. Purification by flash column chromatography on silica gel provides [2-(4-benzoylamino-phenyl)-ethyl]-carbamic acid tert-butyl ester (compound 1.2).
Reaction SMILES: S(Cl)(Cl)=O.[Cl-:5].[Al+3].[Cl-].[Cl-].[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:5])=[O:16])=[CH:13][CH:12]=1
Reactant: [Cl-]
Reactant: COc1ccc(C(=O)O)cc1
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1

Procedure:
2 equivalents of thionyl chloride and 0.1 g of aluminum chloride are added to 10 g (0.06 mole) of 4-methoxybenzoic acid in suspension in 60 ml of petroleum ether. This reaction mixture is refluxed for 5 hours. The solution is concentrated under reduced pressure. The residual oil crystallizes in the presence of petroleum ether at 0° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:47])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([C:43]([F:46])([F:45])[F:44])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:36])([F:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:47])=[CH:17][C:18]=4[C:43]([F:44])([F:45])[F:46])=[N:42][C:27]2=3)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3C(F)(F)F)ncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCNCC4)cc3C(F)(F)F)ncc21
Yield: 82.6 %

Procedure:
A solution of 0.0298 g (0.0446 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-211) in 4 mL of dichloromethane was stirred with 2 mL of trifluoroacetic acid for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.0209 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-piperidin-4-yl-3-trifluoromethyl-benzamide (I-212) as a white solid.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[C@H:17]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:18])=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C@H:17]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH3:18])[CH2:2][O:26]2)=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](OC1CCCCO1)C1(c2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 102.6 %

Procedure:
Trimethylsulfoxonium iodide (67.8 g) was added portionwise to an ice-cooled dispersion of 60% sodium hydride in oil (11.8 g) in dimethyl sulfoxide (450 ml) under nitrogen atmosphere. After stirring for 45 minutes at room temperature, the mixture was again cooled in an ice-water bath. To the mixture was added dropwise a solution of (2R)-4'-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (69 g) in dimethylsulfoxide (100 ml) over the period of 45 minutes, followed by stirring for 2 hours at room temperature. Cold water (600 ml) was added to the reaction mixture, which was then extracted three times with ethyl acetate (400 ml, 300 ml and 300 ml). The combined extracts were washed twice with water (100 ml) and once a saturated aqueous saline solution (100 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure, thereby affording a crude product of 2-(4-chlorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (74.5 g) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccncn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a stirred solution of 4-methylpyrimidine (20.64 g, 0.22 mol) and ethyl 4-fluorobenzoate (36.9 g, 0.22 mol) in dry THF (100 mL) at 0° C. under nitrogen was added lithium bis(trimethylsilyl)amide (1M in THF, 440 mL, 0.44 mol) over a 2 h period. A white precipitate deposited during the addition and this suspension was stirred at room temperature overnight. The reaction was diluted with 100 mL of water and filtered. The filtrate was washed with water (3×) and dried. The solution was diluted with ethyl acetate (100 mL) and the organic phase separated. The aqueous phase was further extracted with ethyl acetate (100 mL). Organic phases were dried (MgSO4) and concentrated and combined with the filtrate to give a combined yield of 47 g (98%) of product. 1H NMR (CDCl3) exists as a 2:1 mixture of enol:keto tautomers: 6 enol form: 5.95 (s, 1H), 6.92 (dd, J=1.2, 5.7 Hz, 1H), 7.06–7.14 (m, 2H), 7.83 (dd, J=5.4, 8.7 Hz, 2H), 8.40 (d, J=5.7 Hz, 1H), 8.8 (s, 1H); keto form: 4.42 (s, 2H), 7.12–7.18 (m, 2H), 7.34 (d, J=4.2 Hz, 1H), 8.06 (dd, J=5.3, 8.8 Hz, 2H), 8.67 (d, J=5.1 Hz, 1H), 9.16 (s, 1H); APESI-MS m/z 215 (M−1)−.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:3]1[S:11]([CH3:14])(=[O:13])=[O:12].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([SH:31])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1.[H-].[Na+]>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([S:31][C@H:4]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]([NH:3][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:1])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: C[C@@H]1[C@@H](c2ccccc2)N1S(C)(=O)=O
Reactant: Fc1ccc(-n2ncc3cc(S)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](NS(C)(=O)=O)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
To (2R,3R)-2-methyl-1-(methylsulfonyl)-3-phenylaziridine (38a, 0.03 g, 0.14 mmol) in THF (4 ml) was added 1-(4-Fluorophenyl)-1H-indazole-5-thiol (37c, 0.038 g, 0.16 mmol) and sodium hydride (5.11 mg, 0.21 mmol) on an ice bath with stirring. The ice bath was removed and the mixture was stirren at room temperature over night. The solvent was removed and the mixture was purified on HPLC. Yield 0.007 g (11%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[C:45]2[C:41]([CH:42]=[C:43]([C:47]([OH:49])=O)[NH:44]2)=[CH:40][CH:39]=1.[NH2:50][CH2:51][C:52]1[C:53]([F:69])=[C:54]([O:59][C:60]2[CH:61]=[C:62]([CH:65]=[C:66]([Cl:68])[CH:67]=2)[C:63]#[N:64])[C:55]([Cl:58])=[CH:56][CH:57]=1>CN(C=O)C>[Cl:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][NH:50][C:47]([C:43]2[NH:44][C:45]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:37][CH2:36][CH2:35][OH:34])[CH:46]=3)=[O:49])=[C:53]([F:69])[C:54]=1[O:59][C:60]1[CH:61]=[C:62]([C:63]#[N:64])[CH:65]=[C:66]([Cl:68])[CH:67]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1cc2ccc(OCCO)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4ccc(OCCO)cc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
HATU (0.070 g, 0.186 mmol) and DIPEA (0.024 mL, 0.186 mmol) were added to a solution 6-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.041 g, 0.186 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.057 g, 0.186 mmol) in DMF. This solution was stirred 2 h at room temperature. The mixture was partitioned between water and EtOAc, the organic layer was separated, washed with a 15% solution of Na2CO3, dried over MgSO4 and filtered. The EtOAc was evaporated to yield a residue which upon trituration in EtOAc afforded the title compound (0.041 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.38 (s, 1H), 8.88 (t, 1H), 7.80 (s, 1H), 7.43-7.53 (m, 4H), 7.37 (t, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 6.68 (d, 1H), 4.83 (t, 1H), 4.53 (d, 2H), 3.94 (t, 2H), 3.71 (q, 2H). MS m/z 512 (M−1).