Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(C(=O)c3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide (0.30 g, 0.95 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in mineral oil, 0.38 g, 0.95 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. To the resulting solution was added 4-fluorobenzoyl chloride (0.11 mL, 0.95 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluted with 60-80% ethyl acetate in hexanes to afford the title compound in 23% yield (0.10 g, 23%): mp 130-132° C.; 1H NMR (300 MHz, CDCl3) δ 7.66-7.61 (m, 2H), 7.29-7.23 (m, 5H), 7.10-7.04 (m, 2H), 5.86 (br s, 1H), 4.49 (d, J=5.5 Hz, 2H), 4.21-4.15 (m, 4H), 2.60 (s, 3H), MS (ES+) m/z 439.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH:8]([CH3:10])[CH3:9].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:14]([O:13][C:12]([NH:11][C@@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])/[CH:5]=[CH:4]/[CH2:3][C:2]([OH:21])=[O:1])=[O:18])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)=O
Reactant: CC(C)C[C@@H](/C=C/CCO)NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)C[C@@H](/C=C/CC(=O)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (5) (1.00 g, 3.89 mmol) in acetone (40 mL) at 0° C. was added a freshly prepared solution of Jones Reagent (2.5 M, 3.89 mL, 9.71 mmol) and the reaction was stirred at 0° C. for 1 h. The dark solution was extracted with Et2O (3×50 mL), the organic layers washed with water (2×75 mL), brine (1×50 mL), dried (Na2SO4), filtered and concentrated to yield 990 mg (94% crude) of acid (6) as a yellow oil that was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.Cl.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[O:22][C:21]([CH2:23][CH2:24][NH2:25])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[O:22][C:21]([CH2:23][CH2:24][NH:25][C:6]([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[O:8])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)c1c[nH]cn1
Agent: Cl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1c[nH]cn1

Procedure:
The title compound was prepared as in Example 12 starting from 4-imidazolecarboxylic acid and 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crude product was purified by flash chromatography using CH2Cl2/MeOH as a gradient eluent (100:0-99.6:0.4). The product was triturated in ethyl acetate. 1H NMR (400 MHz, DMSO-d6): 2.93 (21-1, t), 3.55 (2H, m), 6.33 (1H, d), 7.01 (1H, d), 7.59 (1H, s), 7.63 (2H, s), 7.71 (1H, s), 7.87 (1H, s), 8.05 (1H, broad s), 12.43 (1H, broad s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[CH:7].[F:11][C:12]1[C:13](I)=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])/[C:15]/2=[CH:22]\[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[C:7][C:13]1[C:12]([F:11])=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:22]/[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])/[C:16](=[O:21])[NH:17]2
Reactant: C#CC(C)(C)NC(=O)OC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C)(C)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, (1,1-dimethyl-2-propynyl)-carbamic acid methyl ester (47.7 mg, 0.34 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give (Z)-[3-[2,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-1,1-dimethyl-2-propynyl]carbamic acid methyl ester. (Yield 40 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C:20]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=2)([OH:23])[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCOC1
Product: Cc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylphenyl magnesium bromide (58 ml of a 1M solution in THF, 58.0 mmol) at 0° C. was added a solution of N-t-butoxycarbonyl piperidin-4-one (10.0 g, 53 mmol) in THF (30 ml) dropwise over 20 min, and the reaction stirred under argon for a further 30 min. The reaction was quenched by addition of sat NH4Cl solution (100 ml), and diluted with EtOAc. The organic extracts were dried, (MgSO4) and the solvent evaporated in vacuo to afford the title compound of sufficient purity to be used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]=O)[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH2:14][N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1)[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1c(F)cnc2ccc(=O)n(CC=O)c12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c12
Reaction time: 3 h
Yield: 77.9 %

Procedure:
(8-Ethyl-7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (0.168 g, 0.718 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (0.172 g, 0.860 mmol) was dissolved in CHCl3 (6 ml) and MeOH (0.6 ml) at rt under argon, whereupon NaBH(OAc)3 (0.497 g, 2.34 mmol) was added, after which it was stirred for 3 h. The reaction was then purified by chromatography on silica gel using a 0-20% MeOH in EtOAc gradient to give the title compound as a yellow oil (0.234 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:26]=2[NH2:34])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C(#N)C>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:24](=[O:35])[C:25]3[C:26](=[CH:27][CH:28]=[C:29]([N:31]([CH3:32])[CH3:33])[CH:30]=3)[NH:34][C:37]2=[O:38])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2cc(N(C)C)ccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(-n2c(=O)[nH]c3ccc(N(C)C)cc3c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
There was suspended, in 480 mL of acetonitrile, 47.1 g of 4-{2-amino-5-di-methylamino-benzoylamino}-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine methyl ester synthesized in the foregoing step 1, then 15.9 g of 1,1′-carbonyl-diimidazole (CDI) was added to the suspension and then the mixture was heated at a temperature ranging from 55 to 60° C. for 2.5 hours with stirring. After the completion of the reaction, the mixture was cooled to 5° C. and the resulting crystals were filtered off to thus give 35.6 g of primary crystals. The filtrate and the wash liquid were concentrated to half, then 200 mL of water was added thereto to thus separate out crystals, the resulting slurry was filtered and the resulting crystals were dried to thus give 6.35 g of secondary crystals. The physical properties of the resulting compound were found to be in good agreement with those observed for the same compound prepared in the foregoing synthesis Example.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl.[F:13][C:14]([F:41])([F:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>COCCOC>[F:13][C:14]([F:41])([F:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:36])=[CH:33][CH:32]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Recrystallization from ether affords the product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH:8][C:9]2[C:14]3=[N:15][CH:16]=[C:17]([C:18]#[N:19])[N:13]3[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)=[N:3]1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([N:8]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]2[C:14]3=[N:15][CH:16]=[C:17]([C:18]#[N:19])[N:13]3[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)=[N:3]1
Reactant: CSc1nc(Nc2nc(C)n(C)n2)c2ncc(C#N)n2n1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nc(C)n(C)n2)c2nc(SC)nn3c(C#N)cnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (157 mg, 0.521 mmol) was taken up in DMF (6 mL) under argon and NaH (22.92 mg, 0.573 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, and then alpha-chloro-4-methoxytoluene (0.074 mL, 0.547 mmol) was added. The reaction mixture was heated at 80° C. for 3 h. The reaction was quenched with saturated NaHCO3 solution and extracted 3× with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)(4-methoxybenzyl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (185 mg) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:33])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:33][CH:25]([CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: NCC(O)CN1CCOCC1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (126.6 mg, 0.4 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (74 mg, 0.48 mmol) to precipitate 5-[5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (107 mg, 58%). 1H NMR (DMSO-d6) δ 2.29 (m, 1H), 2.33 (m, 1H), 2.39 (m, 4H), 2.40, 2.42 (2×s, 6H, 2×CH3), 3.15 (s, 1H), 3.37 (m, 1H), 3.55 (m, 4H), 3.77 (m, 1H), 4.74 (d, J=4.8 Hz, 1H, OH), 6.85 (d, J=8.4 Hz, 1H), 7.11 (dd, J=2.0, 8.0 Hz, 1H), 7.53 (t, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.97 (d, J=2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 457.4 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH:26]1([CH2:31]Cl)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:31][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: ClCC1CCCC1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nn(CC3CCCC3)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 42.4 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and cyclopentylmethyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 42.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:8][C:9](=[O:18])[N:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:7])[CH3:6].[CH3:22][O-].[Na+].CI>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:8][C:9](=[O:18])[N:10]([O:17][CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:7])[CH3:6]
Reactant: C[O-]
Reactant: CC(C)(NC(=O)N(O)c1ccccc1)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CON(C(=O)NC(C)(C)c1cccc(Cl)c1)c1ccccc1
Yield: 83.3 %

Procedure:
A solution of 2.2 g of N-phenylhydroxylamine in 10 ml of benzene was added to a solution of 0.02 mole of m-chloro-α,α-dimethylbenzyl isocyanate (prepared from the corresponding cyanide in the same way as in Synthesis Example 1) in 10 ml of benzene. The mixture was stirred well and allowed to stand overnight. The precipitated crystals were filtered off and washed with n-hexane to yield 5.7 g of 3-(m-chloro-α,α-dimethylbenzyl)-1-hydroxy-1-phenylurea. To 3.1 g of the urea was added a solution of 550 mg of sodium methoxide in 10 ml of methanol. The mixture was made homogeneous by stirring and 1.5 g of methyl iodide was added thereto. The mixture was then heated under reflux for 2 hours. The solvent was evaporated off and the residue was extracted with benzene and water was added. The benzene layer was dried over sodium sulfate and the solvent was distilled off to give crystals, which were recrystallized from a mixture of n-hexane and benzene to obtain 2.7 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:25][C:26]([F:39])([F:38])[O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[F:39][C:26]([F:25])([F:38])[O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[C:9]3[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1cc2ccccc2n1-c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-1H-indole-2-carboxylic acid (0.4 g, 1.59 mmol) in 10 mL of 1:1 of dichloromethane/sat. aqueous sodium bicarbonate was added 4-trifluoromethoxy-benzenesulfonyl chloride (0.40 g, 1.53 mmol). After being stirred at room temperature for 1 hour the solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min) to afford 0.105 g (15%) of the title compound as a pale yellow solid: 1H NMR (DMSO-d6) δ 6.89(d, J=8.3 Hz, 1H), 7.10-7.30 (m, 6H), 7.39 (d, J=2.1 Hz, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.71 (d, J=6.0 Hz, 1H), 7.90-8.00 (m, 2H), 10.63 (br s, 1H), 12.74 (br s, 1H); MS (ESI) m/z 477 (MH+); MS (ESI) m/z 475 ([M−H]−); HRMS calcd for C22H16F3N2O5S: 477.0721; found (ESI+): 477.0719; Anal. calcd for C22H15F3N2O5S.0.2H2O: C, 55.05; H, 3.23; N, 5.84. Found: C, 54.97; H, 3.41; N, 5.82.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:34]C(OC(C)(C)C)=O)=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH:31]3[CH2:33][CH2:32]3)[C:14]=2[N:15]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=1B(O)O>>[NH2:34][C:4]1[S:3][C:2]([C:44]2[CH:45]=[C:46]([CH3:49])[CH:47]=[CH:48][C:43]=2[F:42])=[N:6][C:5]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][N:13]([CH:31]2[CH2:32][CH2:33]2)[C:14]=1[N:15]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][NH:18][CH2:17][CH2:16]1)=[O:8]
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(C2CC2)c1N1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C4CC4)c3N3CCNCC(F)(F)C3)c(N)s2)c1
Yield: 53 %

Procedure:
Following the procedure for Example 105, tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate and 2-fluoro-5-methylphenylboronic acid was reacted to give 144 as a beige foam (75 mg, 53% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.92 (dd, J=7.2, 2.2 Hz, 1H), 7.84-7.79 (m, 1H), 7.16-7.11 (m, 1H), 7.10-7.00 (m, 1H), 6.09 (s, 2H), 3.69 (t, J=13.3 Hz, 2H), 3.51-3.35 (m, 5H), 3.09 (t, J=5.5 Hz, 2H), 2.39 (s, 3H), 2.05-1.80 (m, 1H), 1.29-1.19 (m, 2H), 1.09-0.98 (m, 2H). LCMS (ES+) m/z 492 (M+1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[F:23][C:24]1[CH:25]=[C:26]([NH:30]N)[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([N:30]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:27]=[CH:28][CH:29]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(F)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=358.1 (M+H)+
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]=[N+:15]=[N-:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[ClH:17]>>[ClH:17].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]=[N+:15]=[N-:16])(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Reaction time: 0.33 h

Procedure:
The 4-acetylaminobenzenesulfonylazide obtained according to (1) is stirred with 400 g 32-% aqueous hydrochloric acid and the mixture is brought to a temperature of 95° C. within 20 minutes. The substance goes into solution completely. Upon cooling, the hydrochloride of the 4-aminobenzenesulfonylazide crystallizes out from the hot hydrochloric solution and is filtered off.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([C:19]#[C:20][C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CCOC(C)=O.CO>[C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([CH2:19][CH2:20][C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ncccc1-c1cc(C#Cc2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(CCc2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Yield: 56.2 %

Procedure:
step 2—A suspension of 180 (0.322 g, 0.831 mmol) 20% Pd(OH)2/C (0.146 g) and EtOAc/MeOH (1:1, 40 mL) was hydrogenated in a Parr Shaker under 50 psi of hydrogen for 2 h. The resulting suspension was filtered through CELITE and evaporated. The crude product was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 90% EtOAc) to afford 0.183 g of 6-{2-[3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-pyridin-3-ylamine (182) as a yellow foam.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(CC(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCCCCCc1ccc(CC(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5.5 g (25 mmol) of 2-(4-hexylphenyl)acetic acid was dissolved in 11 mL of ethanol and mixed with 1.1 g (11.2 mmol) of sulfuric acid and stirred at 60° C. for 1 hour. The reaction was quenched with cold saturated aqueous sodium carbonate (100 ml), and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 5.68 g of the desired product as a pale yellow oil.