Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[CH3:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2C)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.56 g, 0.008 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (4.90 g, 0.038 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-dimethyl-phenoxy)-but-2-enoic acid ethyl ester (2.40 g, 0.008 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dimethyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (910 mg, 29%) as yellow oil.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:24]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:27][C:26](=[O:42])[NH:25]2)[CH:17]=[C:18]([O:21][CH2:22][CH3:23])[C:19]=1[OH:20].O>C1COCC1>[CH2:22]([O:21][C:18]1[C:19]2[O:20][C:6](=[O:7])[NH:13][C:14]=2[CH:15]=[C:16]([CH:24]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:27][C:26](=[O:42])[NH:25]2)[CH:17]=1)[CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(N)c1O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc2[nH]c(=O)oc12
Yield: 26.8 %

Procedure:
To a solution of CDI (243 mg, 1.50 mmol) in THF (3 mL) was added 4-(3-amino-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one (386 mg, 0.96 mmol) and the resultant mixture was heated to reflux for 1.0 h. The reaction mixture was added water (10 mL) and filtered. The filtered mass was washed with methanol (3 mL) and dried to afford Compound 72 as a yellow solid (110 mg, 30%). 1H NMR (DMSO-d6 500 MHz): δ 11.56 (s, 1H), 8.69 (s, 1H), 7.49 (s, 1H), 7.21 (s, 3H), 7.20 (s, 2H), 6.99-7.04 (m, 3H), 6.81 (d, J=6.0 Hz, 2H), 6.74 (d, J=6.0 Hz, 2H), 5.12 (s, 1H), 4.11 (q, J=6.8 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H); MS (ESI): m/z 428.1 [M+1]+.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:4]([CH3:32])=[C:5]([C:26]([CH3:31])=[C:27]([Cl:30])[C:28]=1[CH3:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:6][C:5]1[C:26]([CH3:31])=[C:27]([Cl:30])[C:28]([CH3:29])=[C:3]([Cl:2])[C:4]=1[CH3:32])[CH3:34]
Reactant: Cc1c(Cl)c(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1Cl
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)c(Cl)c(C)c(Cl)c1C

Procedure:
3,5-dichloro-2,4,6-trimethyl-benzyl-triphenyl-phosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to form 9-(3,5-dichloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to 9-(3,5-dichloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid, m.p: 220°-222° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])=[O:29]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33]([C:32]4[CH:31]=[C:30]([CH:38]=[CH:37][CH:36]=4)[C:28]([O:27][CH3:26])=[O:29])=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COC(=O)c1cccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(methoxycarbonyl)benzoic acid as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:18][CH:17]=1>>[C:9]1([C@H:17]2[C@H:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]([F:26])([F:27])[F:13])=[CH:21][CH:20]=3)[C:23](=[O:24])[NH:25][C:16]2=[O:15])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:20][CH2:19][CH2:18][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccc(OC(F)(F)F)cc1
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(OC(F)(F)F)cc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(4-trifluoromethoxyphenyl) pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 4-trifluoromethoxyphenylacetamide. Yield 67.8 mg, 16.4%. 1H NMR (DMSO-d6) 400 MHz δ: 11.56 (s, 1H), 7.52 (d, 2H, J=8.4 Hz), 7.35 (s, 1H), 7.33 (d, 2H, J=8.0 Hz), 7.15 (d, 1H, J=7.2 Hz), 6.86 (m, 2H), 4.58 (d, 1H, J=8.0 Hz), 4.45 (d, 1H, J=8.0 Hz), 4.10 (t, 2H, J=6.0 Hz), 2.90 (t, 2H, J=6.0), 2.10 (t, 2H, J=5.6).
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].O>[OH:8][CH2:9][C:10]1([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][C:13](=[O:15])[CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(=O)O1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOCCC1(CO)CCC(=O)O1

Procedure:
A mixture containing 10.2 g (21.83 mmol) of the compound prepared in (e) above, 300 ml of a mixture of ethyl alcohol and water in a ratio of 9:1 and 1.5 g of 5% palladium on carbon (50% water content) was placed in a pressure bottle and hydrogenated at 40° C. under a pressure of 50 lbs. of hydrogen until uptake was complete. The catalyst was then filtered off and the filtrate concentrated in vacuo. The residue was crystallized from methanol to yield a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=3[O:26][CH3:27])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>C(O)C.CO>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=3[O:26][CH3:27])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)NCCN1CCc2ccc([N+](=O)[O-])cc2CC1
Solvent: CCO
Solvent: CO
Product: COc1cc(N)ccc1C(=O)NCCN1CCc2ccc(N)cc2CC1

Procedure:
7-Nitro-3-(2-[2-methoxy-4-nitrobenzamido]ethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine (0.52 g) was stirred under a hydrogen atmosphere [344.7 kPa (50 p.s.i.)] in an ethanol/methanol (1:1) solution at room temperature for 3 hours. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to give the title compound as a foam, yield 0.42 g, which was used directly without further purification.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28][C:29](=[O:43])[CH:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][CH3:41])[C:33]2=[O:42])Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCCC1.C(Cl)Cl>[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28][C:29](=[O:43])[C:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][CH3:41])[C:33]2=[O:42])=[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.84 g of triphenylphosphine is added to a solution of 0.63 g of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 1.8 ml of dry tetrahydrofuran, and the mixture is stirred overnight at room temperature under nitrogen. The mixture is diluted with methylene chloride and washed with a cold, saturated, aqueous sodium bicarbonate solution. Additional washing with water, drying over sodium sulphate and concentrating by evaporation in vacuo yield the crude title compound which is purified by chromatography over silica gel with toluene/ethyl acetate (19:1 to 3:1).
Reaction SMILES: [C:1]1([C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16]>O1CCCC1>[C:1]1([C:6]([CH:8]=[CH:9][C:10]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=[O:16])=[O:12])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)C=CC(=O)c1cccs1
Solvent: C1CCOC1
Product: O=C(C=CC(=O)N1CCC[C@H]1C(=O)O)c1cccs1

Procedure:
As for Example 1, 3-(2-thenoyl)acrylic acid (0.01 mole) is coupled to L-proline (0.01 mole) with N,N'-carbonyldiimidazole (0.011 mole) in tetrahydrofuran to give 1-[3-(2-thenoyl)acryloyl]-L-proline.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH2:26]>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:26][C:13](=[O:15])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CNC(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C

Procedure:
To a suspension of 25.9 g (124 mmol) of N-(phenylmethoxycarbonyl)glycine in 370 ml of dichloromethane, were added at 0° C., 0.74 ml of dimethylformamide and 18.8 g (148 mmol) of oxyalylchloride. The mixture was allowed to warm to room temperature and was then added dropwise to a mixture of 19.0 g (124 mmol) of 3,4-dimethoxyaniline (sublimed) and washed with 10% hydrochloric acid solution and twice with water, and dried over sodium sulfate. After the evaporation of the solvent, the residue was triturated with ether and dried in vacuo; yield: 26.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([Cl:19])[CH:11]=3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>C(Cl)Cl>[Cl:19][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([C:17]#[N:18])=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH:7]=[N:6][CH:5]=3)[N:9]2[CH3:20])=[CH:14][CH:13]=1
Reactant: Cn1c(-c2cncc(N)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 211, 85 mg, 0.3 mmol) in DCM (15 mL) is added triethylamine (122 mg, 1.2 mmol) and ethanesulfonyl chloride (77 mg, 0.6 mmol) and the reaction mixture is stirred overnight. The solvent is removed and the residue is redissolved in methanol (15 mL). Aqueous 1M NaOH (1 mL) is added and the reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (methanol in dichloromethane gradient) to give ethanesulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.3 Hz, 3H), 3.23-3.33 (m, 2H), 3.79 (s, 3H), 7.36 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.90 (t, J=2.3 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 8.61 (d, J=2.3 Hz, 2H), 10.43 (s, 1H). HRMS (ESI) m/z 375.0692 [(M+H)+ Calcd for C17H16ClN4O2S: 375.0682].
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C@:5]1([CH2:11][NH:12]C(OC)=O)[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1.[ClH:18]>O1CCOCC1.O>[ClH:18].[NH2:12][CH2:11][C@@:5]1([CH2:4][C:3]([OH:17])=[O:2])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1
Reactant: COC(=O)C[C@]1(CNC(=O)OC)CC[C@@H](C)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@@](CN)(CC(=O)O)C1
Yield: 53 %

Procedure:
[(1S,3R)-1-(Methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester (2.84 g, 11.7 mmol) was refluxed in a mixture of 1,4-dioxane (15 mL) and 6N Hydrochloric acid (30 mL) for 17 hours. The mixture was allowed to cool, diluted with water (200 mL), and washed with dichloromethane (2×100 mL). The aqueous layer was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate/methanol (95:5) to give 1.28 g (53%) of ((1S,3R)-1-aminomethyl-3-methyl-cyclopentyl)-acetic acid hydrochloride;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:10]=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=CO
Product: Brc1ccc2[nH]cnc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4-bromobenzene-1,2-diamine (4.0 g, 21.5 mmol) and formic acid (95%, 100 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to RT and concentrated in vacuo to afford a dark oil. The crude oil was partitioned between EtOAc (500 mL) and NH3/H2O (50 mL). The EtOAc layer was separated and concentrated in vacuo to afford 4.5 g (100%) of 5-bromo-1H-benzo[d]imidazole (78) as brown solid: MS (ESI) m/z=197.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:3]3[C:4]([NH2:9])=[N:5][C:6]([NH2:8])=[N:7][C:2]=3[CH3:1])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1)#[N:22]
Reactant: Cc1nc(N)nc(N)c1N1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Yield: 83.8 %

Procedure:
A mixture of 12.5 g (0.060 mole of 6-methyl-5-(1-piperazinyl)-2,4-pyrimidinediamine, 7.27 g (0.060 mole) of 4-fluorobenzonitrile, and 8.28 g (0.060 mole) of potassium carbonate was heated at 100° C. for two hours in 100 ml of dimethylsulfoxide. The mixture was then cooled and poured into 500 ml of ice water. The solid which separated was triturated with hot dimethylsulfoxide and then dried in vacuo overnight at 67° C. to give 15.56 g of the product as a white solid, mp>310° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:16][C:17]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=3)[CH3:22])=[C:18](O)[N:19]=1)[CH3:14])[CH:7]=[CH:6]2.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:16][C:17]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=3)[CH3:22])=[C:18]([C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:19]=1)[CH3:14])[CH:7]=[CH:6]2
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2cc(C(C)c3nc(O)c(C(C)c4ccc(CC(C)C)cc4)s3)ccc2c1
Solvent: c1ccncc1
Product: COc1ccc2cc(C(C)c3nc(C(=O)c4ccccc4)c(C(C)c4ccc(CC(C)C)cc4)s3)ccc2c1

Procedure:
The desired compound is prepared by treatment of the product of example 45 with benzoyl chloride and pyridine.
Reaction SMILES: O[C:2]1([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH2:24][CH2:25][O:26]CC2C=CC=CC=2)=[C:3]1[C:34]([O:36]C)=[O:35].C(O)C>C(OC(=O)C)C>[OH:26][CH2:25][CH2:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C@@H:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[CH:6]=2)[C@H:2]([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[C@H:3]1[C:34]([OH:36])=[O:35]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCOCc1ccccc1)=C(C(=O)OC)C2(O)c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 83.3 %

Procedure:
A mixture of methyl (1SR)-1-hydroxy-3-[2-(2-benzyloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxy phenyl)-5-propoxyindene-2-carboxylate (88 g, 0.141 moles) 10% palladium on carbon (21 g), 0.65 L of absolute ethanol and 0.65 L of ethylacetate was hydrogenated at 50 psi, 55° C. for 48 hrs. The catalyst was filtered off, and the filtrate concentrated in vacuo to give an amorphous glass. Crystallization from 35OmL of absolute ethanol gave 59.5 g (81%) of white solid; m.p. 165-168° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10](I)[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([O:8][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9])[CH3:11]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Chloro-2-thiophenecarboxylic acid (6.50 g) was dissolved in N,N-dimethylformamide (30 ml), and ethyl iodide (3.2 ml) and potassium carbonate (5.52 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-2-thiophenecarboxylic acid ethyl ester (5.27 g). 5-Chloro-2-thiophenecarboxylic acid ethyl ester (2.23 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room temperature for 48 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired fractions were concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g). 4,5-Dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at 60° C. for 15 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid (2.14 g) as crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])=[CH:12][CH:11]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C@@H:18]([CH3:19])[NH2:20])=[CH:12][CH:11]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
1,1-dimethylethyl [(1R)-2-({6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 39, 29 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (168 μl, 2.179 mmol). The reaction was stirred during 1 hour at 0° C. and 2 hours at room temperature. The reaction mixture was evaporated. The residue obtained was purified by SCX (3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N)). Evaporation of the volatiles, afforded the title compound (21 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:38])([C:34]([F:37])([F:36])[F:35])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[C@:9]([CH3:38])([C:34]([F:35])([F:37])[F:36])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]#[N:32])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(N)=N2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ((2R,5R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (2.27 g, 4.13 mmol) in CH2Cl2 (25 ml) was added TFA (41.3 mmol, 3.18 ml) and the reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was added to 10% aqueous NaHCO3 solution (pH>8) and the free base was extracted with EtOAc. Combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was re-crystallized twice by dissolving the material in EtOH (15 ml) at 50-60° C. and after saturation with H2O (6-8 ml) the clear solution was allowed to cool to ambient temperature overnight to provide after filtration and drying the title compound in >99% purity as white crystals: UPLC RtH5=0.905 min; ESIMS: 450 [(M+H)+]; 1H NMR (600 MHz, DMSO-d6): 10.72 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 7.78 (d, 1H), 7.71 (m, 1H), 7.15 (t, 1H), 6.08 (br s, 2H), 3.91 (d, 1H), 3.78 (d, 1H), 2.52 (s, 3H), 1.46 (s, 3H), 1.41 (s, 3H).