Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([CH2:15][CH3:16])([F:14])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C:12]([CH2:15][CH3:16])([F:14])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:66][CH:63]5[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]5)=[O:30])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CCC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and. 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.4 Hz, 3 H) 1.08-2.06 (m, 16 H) 2.20 (s, 3 H) 2.82 (d, J=11.1 Hz, 2 H) 3.25 (s, 4 H) 3.60-3.85 (m, 3 H) 3.95 (s, 3 H) 4.49 (m, 1 H) 7.47 (d, J=8.3 Hz, 1 H) 7.50 (s, 1 H) 7.77 (s, 1 H) 8.01-8.19 (m, 2 H) 8.31 (d, J=8.3 Hz, 1 H). [M+H] calc'd for C30H42FN7O3, 568; found 568.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][C:47]([NH2:49])=[O:48])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][C:47]([NH2:49])=[O:48])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 7) was coupled with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C35H43N6O3Cl2 [(M+H)+] 665.2768, observed 665.2767.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3cccc(O)c3)nc2N2CCOCC2)O1
Temperature: 120 °C

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (58 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by trituration with diethyl ether affording 109 as a white solid (38 mg, 63%). LCMS: RT=4.13 min, [M+H]+=344. 1H NMR (400 MHz, CDCl3): δ 7.87-7.82 (2H, m), 7.26 (1H, t, J=7.6 Hz), 6.91 (1H, dd, J=2.4, 7.6 Hz), 3.92 (2H, s), 3.90-3.80 (8H, m), 1.47 (6H, s).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([NH2:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[C:4]1[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:5]=1[NH:6]2.[CH2:19]([S:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH3:20].O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[CH2:19]([S:21]([C:24]1[CH:29]=[C:28]([C:2]2[CH:10]=[C:9]([NH2:11])[C:8]([O:12][CH3:13])=[C:7]3[C:3]=2[C:4]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14][C:5]=2[NH:6]3)[CH:27]=[CH:26][CH:25]=1)(=[O:22])=[O:23])[CH3:20]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COc1c(N)cc(Br)c2c1[nH]c1ncc(C)cc12
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cc(N)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 140 °C
Yield: 81.9 %

Procedure:
A 5 mL microwave vial was charged with Compound 238 (500 mg, 1.63 mmol), 3-(ethylsulfonyl)phenylboronic acid (419 mg, 1.96 mmol) and Pd(PPh3)4 (188 mg, 0.16 mmol). To the mixture was added dioxane (5 mL) and a saturated aqueous solution of K2CO3 (2.5 mL). The reaction mixture was heated at 140° C. for 20 min. in microwave. The reaction was diluted with EtOAc and washed with aqueous water and brine. The organic extracts were dried (Na2SO4) and concentrated and purified by flash chromatography to yield the title compound (528 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.33 Hz, 3H) 2.25 (s, 3H) 3.95 (s, 3H) 7.44 (br. s., 1H) 7.78 (br. s., 1H) 7.87 (d, J=7.58 Hz, 1H) 7.96 (d, J=3.28 Hz, 1H) 8.01 (d, J=7.33 Hz, 1H) 8.07 (br. s., 1H) 8.23 (br. s., 1H) 9.88 (br. s., 1H) 12.07 (br. s., 1H); [M+H] calc'd for C21H21N3O4S, 396.2; found, 396.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=[O:35])=[O:29])[CH:5]=[CH:6][CH:7]=1.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:74][C:75]([CH3:79])([CH3:78])[CH2:76]N>C(Cl)Cl>[OH:74][C:75]([CH3:79])([CH3:78])[CH2:76][O:35][C:34](=[O:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:40])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:29])[CH:32]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)CN
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: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OCC(C)(C)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid (80 mg, 0.14 mmol) in methylene chloride (10 mL), HATU (Aldrich, 104 mg, 0.27 mmol) was added followed by the addition of DIPEA (0.41 mmol) and 2-hydroxy-2-methyl-propylamine (Matrix, 24 mg, 027 mmol). The mixture was stirred at rt 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 75 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30].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>CN(C=O)C>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:22]
Reactant: COCCN
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
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: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOC)ccc21
Yield: 39.3 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (68.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methoxy-ethylamine (45.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 431; and 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (1H, br. s), 8.08 (1H, br. s), 7.92 (1H, br. s), 7.76-7.65 (2H, m), 7.51 (1H, m), 7.40-7.38 (1H, m), 4.22 (2H, br. s), 3.50-3.43 (4H, m), 3.29 (3H, s), 1.33-1.30 (3H, t), —NH proton signal was not observed.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(C)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-phenyl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[C:9]#[CH:10])=[C:4]([O:12][CH2:13][S:14][CH3:15])[CH:3]=1.Br[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1/[C:19](=[CH:27]/[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34])/[C:20](=[O:26])[NH:21]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[C:9]#[C:10][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2/[C:19](=[CH:27]/[C:28]2[NH:29][CH:30]=[CH:31][C:32]=2[O:33][CH3:34])/[C:20](=[O:26])[NH:21]3)=[C:4]([O:12][CH2:13][S:14][CH3:15])[CH:3]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc(Cl)cc1OCSC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(Cl)cc3OCSC)c21

Procedure:
Using Method D above, 3-(4-chloro-2-methylsulfanylmethoxy-phenyl)-3-hydroxy-1-propyne (158 mg, 0.65 mmol) (from Example 53 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (152 mg, 0.48 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (40 mg) (Aldrich) and CuI (22 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h, yielding rac-(Z)-4-[3-(4-chloro-2-methylsulfanylmethoxy-phenyl)-3-hydroxy-1-propynyl]-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 132 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[N:3]1[CH2:21][CH2:22][OH:23].[C:25](OC(=O)C)(=[O:27])[CH3:26].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:23][CH2:22][CH2:21][N:3]1[C:2]([CH3:24])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:17])([F:18])[F:19])[CH:9]=2)[C:4]1=[O:20])(=[O:27])[CH3:26]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OCCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 215 mg of the product of Example 43, 15 mg of 4-dimethylamino-pyridine, 1 ml of pyridine and 0.5 ml of acetic acid anhydride was stirred at room temperature for 30 minutes and was then poured into 20 ml of a saturated aqueous sodium bicarbonate solution. After stirring for 20 minutes, the mixture was extracted with ethyl acetate. The organic phase was washed with water and evaporated to dryness and the pyridine and residual acetic acid were distilled. The residue was chromatographed on silica and eluted with a 65-35 methylene chloride-ethyl acetate mixture. The residue with a Rf=0.35 was taken up in isopropanol, partially concentrated, iced and vacuum filtered to obtain after drying 210 mg of the desired product melting at 99° C. to 100° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH3:20])[CH3:11])[CH3:2].C([Li])CCC.Cl[P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>C(OCC)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH3:20])[P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH3:11])[CH3:2]
Reactant: CCc1ccccc1N=C(C)Nc1ccccc1CC
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1ccccc1N=C(C)N(c1ccccc1CC)P(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
N′-(2-ethylphenyl)-N-(2-ethylphenyl)acetamidine (NS Amidine I) (0.798 g, 3.0 mmol) was dissolved in 50 mL of diethylether and cooled to 0° C. Butyllithium (1.50 mL of 2.0 M solution in pentane, 3.0 mmol) was added dropwise, producing a light yellow solution. The solution was warmed to room temperature and stirred for 2 hours. Chlorodiisopropylphosphine (0.48 mL, 3.0 mmol) was added slowly at room temperature. A white suspension formed, which was stirred overnight at room temperature. The slurry was filtered to remove a small amount of white solid, presumably lithium chloride, and the solvent was removed in vacuo to produce 1.14 g (99%) of yellow oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:15][CH2:14]2)(=O)=O)=CC=1.CC(C)([O-])C.[K+].[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[C:30]1([S:36][CH2:11][CH2:12][C:13]2([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH2:14][CH2:15]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(OC3CCCCO3)CC2)cc1
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(SCCC2(OC3CCCCO3)CC2)cc1

Procedure:
2-[1-(2-p-Toluenesulphonyloxyethyl)cyclopropyloxy]tetrahydro-4H-pyran (Compound 4) (1.30 g) was dissolved in a premixed, stirred solution of potassium tert-butoxide (0.45 g) and thiophenol (0.50 g) in N,N-dimethylformamide (10 ml) at room temperature. After a few minutes a precipitate started forming, and after 30 minutes the mixture was partitioned between ether (50 ml) and water. The organic layer was washed consecutively with 2N sodium hydroxide solution, water, and brine. Drying and concentration in vacuo gave a residue which was purified by chromatography (50 g silica gel; 10% ether in petroleum ether as eluant) to give 2-[1-(2-phenylthioethyl)cyclopropyloxy]tetrahydro-4H-pyran. Distillation of a portion gave an analytical sample, b.p. 121°-122° C./0.1 mmHg. (Found: C, 69.07; H, 8.01; S, 11.31. C16H22O2S requires C, 69.03; H, 7.97; S, 11.52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:18][CH:19]([CH2:23][CH2:24][Br:25])[C:20](Cl)=[O:21]>C(OCC)C>[Br:18][CH:19]([CH2:23][CH2:24][Br:25])[C:20]([NH:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:9])=[O:21]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(Cl)C(Br)CCBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C(Br)CCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (S)-1-(4-fluorophenyl)ethanamine (3.2 g, 23 mmol) in diethyl ether (50 mL) and triethylamine (9.6 mL, 69 mmol) at 0° C. was added 2,4-dibromobutanoyl chloride (7.3 g, 27.6 mmole) and the mixture was allowed to warm to rt and stirred for 12 h. A solid formed which was removed by filtration, washed with ethyl acetate, and then discarded. The combined filtrates were evaporated under reduced pressure and the residue was subjected to silica gel chromatography eluting with 20-30% ethyl acetate/petroleum ether yielding 4.5 g of 2,4-dibromo-N—((S)-1-(4-fluorophenyl)ethyl)butanamide as a brown solid. LCMS (method O) RT=0.99 min, m/z 366, 368, 370 (M+H+, M+H++2, M+H++4); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.44 (m, 3H) 2.27-2.46 (m, 2H) 3.46-3.58 (m, 2H) 4.55-4.66 (m, 1H) 4.81-5.00 (m, 1H) 7.03-7.24 (m, 2H) 7.30-7.45 (m, 2H) 8.89 (d, J=8.03 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:8]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH2:13][NH2:14])[CH:10]=[C:9]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCOCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCOCC2)c1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
A solution of nitrile 26B (1.33 g, 4 mmol) in diethyl ether (30 mL) was added in small amounts to a mixture of LiAlH4 (305 mg, 2 mol eq) in diethyl ether (20 mL) stirred at 0° C. After the addition was completed, the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed at 0° C. by addition of small amount of water (30 mL), the solid formed was filtered off and the organic filtrate was separated, washed with brine (50 mL) and dried over Na2SO4. The organic phase was evaporated under reduced pressure to afford 27B as a pale yellow oil (1.34 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 3.54 (m, 4H), 3.76 (m, 6H), 6.87 (s, 1H), 7.38 (s, 1H), 7.81 (d, 2H, J=8), 8.27 (d, 2H, J=7.9).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:11](=[O:32])[N:10]2[S:40]([CH3:39])(=[O:42])=[O:41])=[C:5]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(S(C)(=O)=O)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (260 mg, 500 μmol) was initially charged in dry THF (10 ml), and sodium hydride (60% in mineral oil; 28 mg, 700 μmol; 1.4 eq.) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of methanesulfonyl chloride (80 mg, 700 μmol; 1.4 eq.) in THF (2 ml) was then slowly added dropwise. After a reaction time of 20 h, the reaction mixture was concentrated and the residue was subjected to flash chromatograpy on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 55:45). The title compound was obtained as a colorless solid (288 mg, 96% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[O:9]([CH3:11])[Na].O>CS(C)=O>[CH3:11][O:9][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: CO[Na]
Reactant: Cc1ccnc(Cl)c1
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C)ccn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 46.8 %

Procedure:
A mixture of 2-chloro-4-methylpyridine (20 g, 0.156 mol) and NaOCH3 (9.3 g, 0.172 mol) in DMSO (200 mL) was stirred at 100° C. for 4 hours. The solution was added to H2O and then extracted with ethyl acetate (50 mL×2). The organic layer was washed with H2O (300 mL) brine (300 mL) and dried concentrated to give 2-methoxy-4-methylpyridine (9 g, 46%). LC-MS: 124 [M+H]+, tR=1.21 min.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][CH2:15][CH3:16])[N:8]=[CH:9]2)=[C:2]=[S:3].[OH:17][CH2:18][CH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>C(O)C>[OH:17][CH2:18][CH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][CH2:15][CH3:16])[N:8]=[CH:9]2
Reactant: CCCc1cc2c(N=C=S)cccc2cn1
Reactant: OCCC1Cc2ccccc2CN1
Solvent: CCO
Product: CCCc1cc2c(NC(=S)N3Cc4ccccc4CC3CCO)cccc2cn1
Temperature: 20 °C
Reaction time: 20 h
Yield: 71.3 %

Procedure:
5-Isothiocyanato-3-propylisoquinoline (4.5 g) is added to a solution of (RS)-3-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (3.5 g) in absolute ethanol (35 cc). After stirring for 20 hours at a temperature of about 20° C., the crystals which have appeared are filtered off and then washed with ethanol (2×2 cc). (RS)-3-(2-Hydroxyethyl)-N-(3-propylisoquinol-5-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (5.7 g) is thus obtained; after recrystallisation from propanol (50 cc), it melts at 175° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=O)[C:8]=2[C:14]([F:17])([F:16])[F:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]=[N:19][OH:20])[C:8]=2[C:14]([F:17])([F:16])[F:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1noc(-c2ccccc2)c1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=Cc1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde (step B, 0.415 g, 1.721 mmol), hydroxylamine hydrochloride (0.179 g, 2.58 mmol), and sodium acetate (0.212 g, 2.58 mmol) in methanol (5 mL) was heated at reflux for 45 min. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in water (10 mL), and the solid was collected by vacuum filtration, washed with water (2×5 mL), and dried overnight under reduced pressure to give 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbaldehyde oxime (0.360 g, 1.41 mmol, 82% yield). The compound had an HPLC ret. time=2.43 min. (condition A); LC/MS M+1=256.9.