Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2,6-dichloropyrazine (150 mg, 1.007 mmol) in 1,4-dioxane (1.0 mL) was added 1-methylpiperazine (121.0 mg, 0.13 mL, 1.208 mmol) followed by triethylamine (203.8 mg, 0.281 mL, 2.014 mmol). The reaction mixture was stirred at room temperature for 24 h then concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C9H14ClN4 (M+H+): 213.1; Found: 213.2 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH2:2][C:3]#[CH:4].[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[C:13]1=[O:22])[CH2:19]2>C1COCC1>[I:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][C:3]#[C:4][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH:13]2[OH:22])[CH2:19]3)=[CH:10][CH:9]=1
Reactant: C#CCCc1ccc(I)cc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Product: OC1C2CC3CC(C2)CC1(C#CCCc1ccc(I)cc1)C3
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of 1-(but-3-ynyl)-4-iodobenzene (0.36 g, 1.48 mmol) in anhydrous THF (0.5 ml) 2.8 M MeMgBr in THF (0.6 ml) was added at 0° C. under N2. After stirring for 0.5 h, the solution of 2-admantanone (0.24 g, 1.6 mmol) was added drop wise. This was stirred for 2 h at room temperature, than quenched with the solution of NH4Cl. The mixture was extracted with Et2O. The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2) to give the title product (0.34 g; 56%), as the creamy paste. 1H-NMR (CDCl3) 2.14-2.23 (m, 16H); 4.69 (s, 2H); 6.74 (d, 2H, J=6.87 Hz); 7.54 (d, 2H, J=6.81 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.B1([C:40]2[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=2)OCCCO1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 85.4 %

Procedure:
tert-Butyl 4-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (12.79 g, 24.67 mmol) and pyrdine-3-boronic acid 1,3-propanediol cyclic ester (4.42 g, 27.14 mmol) were coupled according to the method described in Examples 118–121. The work-up procedure described in Part F of Examples 125–135 was followed. The crude product was recrystallized twice from ethyl acetate to provide 10.89 g of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white solid, mp 197–198° C.
Reaction SMILES: CC(N[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:28]=[CH:27][CH:26]=[CH:25][C:12]=1[C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2)=[O:14])(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13](=[O:14])[C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]=3[O:10][CH2:9][CH2:8][CH2:7][CH2:6][N:46]3[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][C:33]4[CH:32]=[C:31]([O:30][CH3:29])[C:36]([O:37][CH3:38])=[C:35]([O:39][CH3:40])[CH:34]=4)[CH2:44][CH2:45]3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: CC(C)(C)NCCCCOc1ccccc1C(=O)Nc1cccc2[nH]ccc12
Reactant: COc1cc(CCN2CCNCC2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CCN2CCN(CCCCOc3ccccc3C(=O)Nc3cccc4[nH]ccc34)CC2)cc(OC)c1OC
Yield: 90.8 %

Procedure:
2.5 g of 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide of Example 33, 2.71 g of 1-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazine [German Patent No. 3,347,173] and 0.683 g of sodium carbonate in 25 ml of ethanol were heated to 60° C. for 10 hours and the mixture is cooled and poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvents were evaporated under reduced pressure. The residue was chromatographed over silica (eluant: chloroform/acetone/triethylamine 6:3:1) to obtain 3.51 g of N-(1H-indol-4-yl)-2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]-1-piperazinyl]butoxy]benzamide.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.C([O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][N:12]=1)=O)C>C(O)C>[CH2:1]([NH:3][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][N:12]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: CCN
Solvent: CCO
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of ethylamine in methanol solution (2.0M; 40 mL; 80 mmol) was added to a stirred suspension of 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethyl ester (4.40 g; 9.51 mmol) in absolute ethanol (50 ml). The reaction mixture was heated to 80° C. (oil-bath temperature) for five hours. The reaction mixture was allowed to cool to ambient temperature and left to stand overnight. A colourless solid product formed and the reaction mixture was further cooled in an ice-water bath, filtered and washed with cold ethanol (2×20 ml). The colourless product was dried in vacuo to afford 5-(2,4-bis-benzyloxy-5-chlorophenyl)-isoxazole-3-carboxylic acid ethylamide 3.42 g (78%) LCMS: [M+H]+ 465, 463 (37Cl; 35Cl). 1H NMR (400 MHz, CDCl3) δ 1.25 (t, 3H), 3.48 (m, 2H), 5.10 (s, 2H), 5.2 (s, 2H), 6.59 (s, 1H), 6.83 (bit, 1H), 7.08 (s, 1H), 7.30-7.41 (m, 10H), 7.97 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1Br)NCc1ccccc1
Reaction time: 2 h

Procedure:
To a stirring solution of 2-bromophenylacetic acid in dichloromethane (0.2 M) was added benzylamine (1.2 eq), triethylamine (1.5 eq), and EDAC (1.5 eq). After 2 hrs, the solution was washed with water, 10% HCl, 10% sodium carbonate, and water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a colorless solid. EI-MS m/z 304/306 (M+H)+
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@H:34]([CH2:37][O:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[N:33](C(OC(C)(C)C)=O)[CH2:32]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C@@H:4]([C:5]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=2[CH2:29][CH2:30][C@H:31]2[O:36][CH2:35][C@@H:34]([CH2:37][O:38][C:39](=[O:40])[NH:41][CH2:42][C:43]([F:45])([F:46])[F:44])[NH:33][CH2:32]2)=[O:7])[NH2:1])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)C1CCOCC1
Product: N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(F)cc1)C1CCOCC1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 89 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=630 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:11][C@H:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C@@H:14]([NH:23][CH2:24][C@@H:25]([OH:49])[C@@H:26]([NH:36][C:37](=[O:48])[C@@H:38]([N:42]2[CH2:46][CH2:45][CH2:44][C:43]2=[O:47])[CH2:39][CH:40]=[CH2:41])[CH2:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[CH2:13]1)C=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[F:35][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([F:34])[CH:31]=1)[CH2:27][C@@H:26]1[NH:36][C:37](=[O:48])[C@@H:38]([N:42]2[CH2:46][CH2:45][CH2:44][C:43]2=[O:47])[CH2:39][CH:40]=[CH:41][CH2:8][O:11][C@@H:12]2[CH2:13][C@@H:14]([C:15]3[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][C:20]=32)[NH:23][CH2:24][C@H:25]1[OH:49]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CC=C)N2CCCC2=O)c2cc(OC)ccc21
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[C@@H]1C[C@H]2OCC=CC[C@H](N2CCCC2=O)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN1
Yield: 70 %

Procedure:
Step I (2): The TFA salt of (S)—N-((2S,3R)-4-((1S,3R)-3-(Allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(2-oxopyrrolidin-1-yl)pent-4-enamide (diastereomer A, 10 mg, 0.0143 mmol) from stepG(1) was dissolved in 2 mL of CH2CL2. Added Hoveyda/Grubbs catalyst [(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(O-isoproproxylphenylmethylene)ruthenium] (2.4 mg, 2.9 μmol, Aldrich) and stirred at room temperature overnight. Evaporated to dryness. Dissolved in MeOH and filtered. The crude product was purified using reverse phase preparatory HPLC to give 5.5 mg (70% yield) of the title compound as its TFA salt: LC-MS (M+H)+=556.31; HRMS (M+H)+=556.2603; 1H NMR (500 MHz, CDCl3) δ 7.27-7.43 (m, 1H), 7.04-7.21 (m, 1H), 6.99 (d, J=8.24 Hz, 1H), 6.40-6.83 (m, 3H), 5.42-5.79 (m, 2H), 4.98 (d, J=5.49 Hz, 1H), 4.71 (d, J=5.49 Hz, 1H), 4.25-4.51 (m, 1H), 4.06 (d, J=8.24 Hz, 1H), 3.87-4.06 (m, 2H), 3.72-3.91 (m, 3H), 3.36-3.72 (m, 3H), 3.16-3.39 (m, 2H), 3.06-3.21 (m, 1H), 2.92-3.08 (m, 1H), 2.76-2.89 (m, 1H), 2.54-2.76 (m, 2H), 2.17-2.54 (m, 3H), 1.86 (dd, J=14.34, 7.32 Hz, 2H), 0.91-1.52 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[C:8]([F:14])[C:7]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=[C:8]([F:14])[C:7]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Cc1c(F)nc(F)c(F)c1OC(C)(C)C
Solvent: CCO
Product: Cc1c(F)nc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1OC(C)(C)C

Procedure:
4-t-Butoxy-2,5,6-trifluoro-3-methylpyridine from Step 253c above is reacted with dibenzylamine in ethanol at reflux temperature. Solvent is removed, and the residue is dissolved in methylene chloride and washed with water. The product is purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2Cl)c1Br
Yield: 66 %

Procedure:
2,3,4-Trichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,3,4-trichlorobenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 110°-113° C., yield 66%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[C:13]([CH2:17][C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:31]=[C:32]=[O:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:32]([NH:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:33])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](=[O:19])[NH2:20])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CC(N)=O)c2)n1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(N)=O)c2)n1
Yield: 68.3 %

Procedure:
A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH2Cl2 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield 1-{3-tert-butyl-1-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-yl}-3-(naphthalene-1-yl)urea as a white solid (0.22 g). mp: 230 (dec.); 1H NMR (200 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.92 (s, 1H), 8.32–8.08 (m, 3H), 7.94–7.44 (m, 8H), 6.44 (s, 1H), 3.51 (s, 2H), 1.31 (s, 9H); MS:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[C:26]([C:31]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]5[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([F:51])([F:50])[F:49])=[CH:42][CH:41]=5)[CH2:35][CH2:34]4)=[O:32])[N:27]3[CH3:30])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:11].[H-].[Na+].I[CH3:55].O>CN(C=O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([N:13]([CH3:55])[C:14]1[CH:15]=[N:16][C:17]([O:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[C:26]([C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:39][C:40]5[CH:41]=[CH:42][C:43]([O:46][CH2:47][C:48]([F:50])([F:49])[F:51])=[CH:44][CH:45]=5)[CH2:37][CH2:38]4)=[O:32])[N:27]3[CH3:30])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2ccc(Oc3ccc4cc(C(=O)N5CCN(Cc6ccc(OCC(F)(F)F)cc6)CC5)n(C)c4c3)nc2)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(C)c2ccc(Oc3ccc4cc(C(=O)N5CCN(Cc6ccc(OCC(F)(F)F)cc6)CC5)n(C)c4c3)nc2)c(C)c1
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
To a solution of 2,4,6-trimethyl-N-[6-(1-methyl-2-{4-[4-(2,2,2-trifluoroethoxy)benzyl]piperazine-1-carbonyl}-1H-indol-6-yloxy)pyridin-3-yl]benzenesulfonamide (0.38 g, 0.53 mmol) in DMF (4 mL) was added 60% sodium hydride in oil (0.025 g, 0.63 mmol) under ice cooling and stirred for 10 minutes. Then to the mixture was added iodomethane (0.036 mL, 0.58 mmol) at 0° C. and the mixture was stirred for 2 hours. Water (8 ml) was added to the reaction mixture and extracted with AcOEt, the organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (AcOEt to AcOEt:MeOH=95:5) to give 0.28 g of the title compound as a colorless amorphous powder.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:9]=2[N:10]=1.[H][H]>[Pd].CCO.C1COCC1>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]([CH3:18])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: [H][H]
Reactant: CN(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Yield: 79.5 %

Procedure:
Combine N,N,N′-Trimethyl-N′-(6-nitro-benzothiazol-2-yl)ethane-1,2-diamine (5.79 g, 20.6 mmol) and 5% palladium on carbon (5.02 g) in EtOH (200 mL) and THF (25 mL). Shake on a Parr shaker at 60 psi of hydrogen at room temperature for 18 h. Filter the reaction mixture through filter paper, wash with EtOH (50 mL), and concentrate in vacuo to afford the crude title compound (4.1 g, 80%). The crude product was carried on as is. 1H NMR (400 MHz, DMSO-d6): δ 7.10 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=1.8 Hz), 6.52 (dd, 1H, J=8.4, 2.2 Hz), 4.80 (br s, 2H), 3.51 (t, 2H, J=6.6 Hz), 3.04 (s, 3H), 2.48 (m, 2H), 2.18 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:30][N:31]([CH:37]1[CH2:39][CH2:38]1)[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[C:9]([N:11]1[C@H:15]([C:16]([NH:18][C@:19]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C@H:20]2[CH:22]=[CH2:23])=[O:17])[CH2:14][C@@H:13]([OH:29])[CH2:12]1)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:45](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]([CH2:30][N:31]([CH:37]1[CH2:39][CH2:38]1)[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[C:9]([N:11]1[C@H:15]([C:16]([NH:18][C@:19]2([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C@H:20]2[CH:22]=[CH2:23])=[O:17])[CH2:14][C@@H:13]([O:29][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:12]1)=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCCCN(C[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCCCN(C[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a mixture of compound 1c (1.55 g, 2.75 mmoL) in 10 mL of DMF was added imidazole (0.47 g, 6.88 mmoL) and tert-butyldimethylsilyl chloride (826 mg, 5.50 mmoL). The mixture was stirred at rt for 18 h, concentrated in vacuo, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, and concentrated in vacuo to obtain an off-white solid. Flash chromatography (eluting with methylene chloride and then ethyl acetate) gave (1R,2S)-ethyl 1-((3R,5S)-1-((S)-2-(tert-butoxycarbonyl)-3-(cyclopropyl(pent-4-enyl)amino)propanoyl)-3-(tert-butyldimethylsilyloxy)pyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate 1d as a white solid (1.75 g, 94%): LC-MS (Phenomenex 10 μm C18 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 2 min. Hold time: 1 min. Flow rate: 5 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.51 min), MS m/z 677 (M++1).
Reaction SMILES: C[C:2]1[N:3]=CN[C:6]=1[CH2:7]SCCN.C(C=C(OC)OC)#N.[C:20]([CH:22]=[C:23](OC)[NH:24][CH2:25][CH2:26][S:27][CH2:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1[CH3:34])#[N:21].C(N)C#C>>[C:20]([CH:22]=[C:23]([NH:3][CH2:2][C:6]#[CH:7])[NH:24][CH2:25][CH2:26][S:27][CH2:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1[CH3:34])#[N:21]
Reactant: COC(=CC#N)NCCSCc1[nH]cnc1C
Reactant: Cc1nc[nH]c1CSCCN
Agent: C#CCN
Agent: COC(=CC#N)OC
Product: C#CCNC(=CC#N)NCCSCc1[nH]cnc1C

Procedure:
When 2-[(4-methyl-1H-imidazol-5-yl)methylthio] ethylamine is reacted with 1-cyano-2,2-bis(methoxy)ethylene according to the procedure of Example 6, Step A, and the resultant 1-cyano-2-methoxy-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene is treated with propargylamine by the procedure of Example 6, Step B, the title compound is produced.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.C(OCC)C>[Si:14]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16]
Reactant: Cc1ccc(O)cc1I
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-iodo-4-methylphenol 1-1 (500 mg, 2.14 mmol), tert-butyldimethylchlorosilane (387 mg, 2.57 mmol) and imidazole (175 mg, 2.57 mmol) in 11 mL of DMF was stirred at rt for 16 h, and then diluted with diethylether, washed with water, brine, dried (MgSO4) and evaporated. The residue was subjected to MPLC on a 40 g column of SiO2 eluting with hexanes to provide 5-tert-butyldimethylsilyloxy-2-methylphenyliodide 1-2 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 0.17 (s, 6H), 0.93 (s, 9H), 2.29 (s, 3H), 6.81 (dd, 1H, J=8, 2 Hz), 7.20 (d, 1H, J=8 Hz), 7.28 (d, 1H, J=2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:11][CH:12](Br)[CH2:13][C:14]([Cl:17])([F:16])[F:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([CH2:11][CH2:12][CH2:13][C:14]([Cl:17])([F:16])[F:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(CC(Br)CC(F)(F)Cl)C(=O)OCC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCC(F)(F)Cl)C(=O)OCC

Procedure:
65.9 g of 2-(2-bromo-4-chloro-4,4-difluoro-but-1-yl)malonic acid diethyl ester, 600 ml of ethanol, 14.8 g of sodium acetate and 6.6 g of 5% palladium on activated carbon are treated with hydrogen at from 20° to 25° and under normal pressure until the absorption of hydrogen can no longer be detected. The reaction mixture is filtered over silica gel and then concentrated to dryness by evaporation in a rotary evaporator. The residue is taken up in 500 ml of n-hexane, the solution is filtered and the hexane phase is again concentrated to dryness by evaporation. The title compound is obtained in the form of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1Br.[C:22]([Cu])#[N:23].CCOC(C)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Br)c2)C1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(C#N)c2)C1
Temperature: 160 °C
Reaction time: 5 h
Yield: 20.6 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (3.76 g) in NMP (30 ml) was added CuCN (1.77 g) and the reaction mixture was then stirred at 160° C. for 5 h. The mixture was then cooled to room temperature and poured into EtOAc. The resulting suspension was filtered through sintered glass and the filtrate was extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in heptane) to afford tert-butyl (RS)-2-(4-amino-3-cyanophenyl)morpholine-4-carboxylate (659 mg, 21%) as a yellow solid. MS (ISP): 321.2 ([M+NH4]+), 304.2 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].N1CCCCC1>>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1)[CH3:20]
Reactant: CCOC(=O)CC#N
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1

Procedure:
Alternatively, compounds of Formula III can be prepared as shown in Schemes 3 and 4. Condensation of 3,5-dimethoxybenzaldehyde with ethyl cyanoacetate in the presence of a base such as piperidine produces the 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester. Treatment of the ester with 3-methoxyphenol in the presence of NaH produces the 3-cyano-7-methoxy-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene. Similarly, reaction of 3-(3-methoxy-phenyl)-2-cyano-acrylic acid ethyl ester with 4-hydroxyindole produces 3-cyano-4-(3-methoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene.