Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][C:12]=3[F:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 17.6 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (150 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (219 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 4, the title compound (44 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2nccn2C)cc(C)c1Cl
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nccn6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-chloro-3,5-dimethyl-phenyl)-1-methyl-imidazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.02 min; Mass spectrum (ESI+): m/z=527 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]1.[C:13]1([C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N+]=[N-])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[C:13]1([CH:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:8][C:7]([CH:5]2[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]2)=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C1CC(C(=O)O)C(C(=O)O)O1
Solvent: CC(C)=O
Product: O=C1CC(C(=O)O)C(C(=O)OC(c2ccccc2)c2ccccc2)O1
Yield: 32 %

Procedure:
262 mg of (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylic acid in 5 ml of acetone was stirred with 291 mg of diphenyldiazomethane at room temperature for 20 minutes. The reaction solution was evaporated in vacuo to dryness. The residue was purified by silica gel column chromatography [chloroform/methanol=100/1→10/1] to give 163 mg of the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][N:28]=1)[C:22]([NH:24][NH2:25])=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:16]1[NH:25][N:24]=[C:22]([C:21]2[CH:26]=[CH:27][N:28]=[C:19]([NH2:18])[CH:20]=2)[N:17]=1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Reactant: NNC(=O)c1ccnc(N)c1
Solvent: CN(C)C=O
Product: Nc1cc(-c2n[nH]c(-c3nc(-c4cccc(CO)c4)cnc3N)n2)ccn1
Temperature: 180 °C
Yield: 5.8 %

Procedure:
To a solution of of 3-amino-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carbonitrile (250 mg, 1.11 mmol) was added 2-aminoisonicotinic acid hydrazide (311 mg, 2.04 mmol). After being heated at 180° C. for 90 min, the reaction mixture was dissolved in DMF and washed with water, ethyl acetate (10 mL×3). The aqueous phase was extracted once with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave a crude oil, which was purified by preparative HPLC to yield (3-{5-amino-6-[3-(2-aminopyridin-4-yl)-1H-1,2,4-triazol-5-yl]pyrazin-2-yl}phenyl)methanol (23.2 mg, 5.7% yield): 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.15 (s, 1H), 8.10 (m, 1H), 7.70 (m, 2H), 7.43 (m, 2H), 7.20 (m, 1H), 6.10 (s, 2H), 5.25 (m, 1H) 4.60 (m, 1H); MS (EI) for C18H16N8O: 361.11 (MH+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:29])([F:28])[C:12]([C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][C@H:20]([C:25]([OH:27])=O)[CH2:19][CH2:18][C:17]=2[N:16]=1)([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:55][C@@H:56]([C:58]1[C:63]([F:64])=[CH:62][C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])=[C:60]([CH3:70])[CH:59]=1)[CH3:57]>CN1CCCC1=O>[F:64][C:63]1[CH:62]=[C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[C:60]([CH3:70])=[CH:59][C:58]=1[C@H:56]([NH:55][C:25]([C@@H:20]1[CH2:19][CH2:18][C:17]2[N:16]=[C:15]([C:12]([CH3:14])([CH3:13])[C:11]([F:29])([F:10])[F:28])[CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:27])[CH3:57]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)[C@@H]2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 60.6 %

Procedure:
N-methylpyrrolidinone (1.2 mL) and N,N-diisopropylethylamine (87 uL, 0.50 mmol) were added to (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (47 mg, 0.16 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (75 mg, 0.20 mmol) in a 4 mL vial, and the mixture stirred at room temperature for 10 min, before a solution of (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (55 mg, 0.19 mmol) in N-methylpyrrolidinone (0.5 mL) was added. After 30 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (50 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (br s, 1H), 8.39 (d, J=8.1 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.06 (d, J=11.7 Hz, 1H), 5.10 (app pentet, J=7.2 Hz, 1H), 3.00 (s, 3H), 2.93-2.76 (m, 4H), 2.68-2.59 (m, 1H), 2.25, (s, 3H), 2.09-2.03 (m, 1H), 1.88-1.76 (m, 1H), 1.54 (s, 3H), 1.35 (d, J=7.0 Hz, 3H); m/z=515.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cn1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CS(C)=O
Product: COC(=O)c1cn(-c2ccccc2)cn1
Yield: 54.9 %

Procedure:
A stirred solution of 1H-imidazole-4-carboxylic acid (0.5 g, 0.00446 mmol), concentrated sulfuric acid (0.5 mL) and MeOH (20 mL) was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate and washed the organic layer with sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 325 mg (58% Yield) of 1H-imidazole-4-carboxylic acid methyl ester. A mixture of 1H-imidazole-4-carboxylic acid methyl ester (225 mg, 1.8 mmol), cuprous oxide (225 mg, 1.8 mmol), iodobenzene (736 mg, 3.6 mmol), 1,10-phenanthroline (320 mg, 1.8 mmol) and cesium carbonate (1.74 g, 5.3 mmol) in DMSO (2 mL) in a seal tube was subjected to reaction in a microwave reactor (time: 5 min, temp: 90° C., power: zero) The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to afford the residue. Purification by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 200 mg (55% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid methyl ester. LiOH.H2O (143 mg, 3.4 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid methyl ester (231 mg, 1.1 mmol) in a mixture of THF (3 mL), MeOH (1 mL), H2O (1 mL) and stirring was continued at ambient temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure. Cold water was then added and acidified it with 10% aqueous HCl, the solid was collected to afford 180 mg (83.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]([O:18]C)=[O:17])=[CH:14][N:15]=2)[CH2:7]1.[OH-].[Na+]>C1COCC1.CO>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=2)[CH2:7]1
Reactant: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carboxylate (1.2 g, 3.2 mmol) and 1M aqueous NaOH (6.4 mL, 6.4 mmol) in THF-MeOH (1:1, 24 mL) was heated at 80° C. bath for 2 h. Volatile solvents were removed in vacuo. The residue was diluted with H2O, acidified with 1M HCl (7 mL) and extracted with EtOAc. The EtOAc extract was washed with H2O, dried (Na2SO4), concentrated and triturated with Et2O to give the title compound as white solid. 1H NMR (400 MHz, acetone-d6): δ 7.84 (s, 1 H), 7.67 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.51 (s, 1 H), 3.95 (m, 1 H), 3.81-3.60 (m, 3 H), 2.60-2.40 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(O)c(N)c1
Yield: 994 %

Procedure:
To a solution of 2-nitro-4-cyanophenol (10 g, 6 mmol) in methanol (250 mL) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/CH2CH2) gave the desired product (8.0 g, 97%). 1H NMR (CD3OD): d 6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H).
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-].CO>C(OCC)(=O)C>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH2:21][CH3:22])(=[O:19])=[O:20])=[CH:16][CH:17]=2)[C:4]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CNC(N)=O
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)NC(=O)NC)cc1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl ester (500 mg, 1.48 mmol) and methyl urea (274 mg, 3.70 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 6.5 mL, 4.43 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 2 d. The reaction mixture was allowed to cool to 25° C. and then diluted with ethyl acetate (25 mL). The mixture was filtered through a pad of celite, and the celite pad was washed with ethyl acetate (50 mL). The resulting filtrate was washed with water (40 mL) then the water layer was further extracted with ethyl acetate (40 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a colorless oil. The oil was treated with a solution of 2/1 hexanes/ethyl acetate (10 mL), and a white solid began to precipitate. The suspension was placed in the freezer to enhance crystallization. The solid was filtered to afford 1-[3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionyl]-3-methyl-urea (178 mg, 33%) as a white solid: mp 200-201° C.; FAB-HRMS m/e calcd for C18H26N2O4S (M+H)+367.1691, found 367.1697.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH2:25]([NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH3:26]>>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:27]([CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH2:25][CH3:26]
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CCNCCN(C)C
Product: CCN(CCN(C)C)Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and N′-ethyl-N,N-dimethyl-ethane-1,2-diamine to give a yellow solid. MS m/z: 434.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][OH:13])=[CH:16][CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Cc2ccc(CO)cc2)c1
Temperature: 85 °C
Yield: 80.8 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (550 mg, 0.476 mmol) is added to a mixture of 3-bromomethyl-benzoic acid methyl ester (3.0 g, 13.09 mmol) and 4-(hydroxymethyl)-phenylboronic acid (2.99 g, 19.68 mmol) in a mixture of toluene (125 mL) and 2M sodium carbonate (62 mL). The mixture was degassed, placed under nitrogen and heated at 85° C. for 16 hours. After cooling to room temperature, the mixture is concentrated in vacuo and the black residue is partitioned between saturated sodium bicarbonate and dichloromethane. After the layers are separated, the aqueous layer is extracted two more times with dichloromethane. The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography (20% tetrahydrofuran in hexanes) to give 2.71 g of the title compound as a yellow oil: MS (m/z): 239 (M−OH); 1H NMR (CDCl3) δ 7.92 (m, 2H), 7.42-7.36 (m, 2H), 7.34-7.29 (m, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.69 (s, 2H), 4.05 (s, 2H), 3.93 (s, 3H), 1.79 (s, 1H).
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][NH:30][CH2:29][C:28](=[O:32])[N:27]([CH2:33][CH3:34])[C:26]=3[CH:35]=2)[N:15]=1)=[O:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCCl>[CH3:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][N:30]([CH2:1][CH3:2])[CH2:29][C:28](=[O:32])[N:27]([CH2:33][CH3:34])[C:26]=3[CH:35]=2)[N:15]=1)=[O:7]
Reactant: CC=O
Reactant: CCN1C(=O)CNCc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCN1CC(=O)N(CC)c2cc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)ccc2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
Acetaldehyde (20 mg, 0.45 mmol) was added to a solution of 3-[5-chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (42.5 mg, 0.09 mmol) in THF:DCE (1:2) at 0° C. After 15 minutes, 100 mg of sodium triacetoxyborohydride was added and the mixture was stirred for 2 hours at 0° C. and 1 hour at room temperature. Evaporation and chromatography on preparative TLC with methylene chloride and methanol (100:7) gave 31 mg of 3-[5-chloro-2-(1,4-diethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide (50%): 1H NMR (300 MHz, CD3OD) δ 8.42 (d, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.44 (d, 1H), 7.42 (s, 1H), 7.27 (d, 1H), 3.9 (q, 2H), 3.64 (s, 2H), 3.22 (s, 2H), 2.87 (s, 3H), 2.75 (q, 2H), 2.05 (s, 3H), 1.18 (m, 6H); MS (m/e): 500.4 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([C:26]([NH:28][CH2:29][CH2:30]O)=[O:27])[N:23]([CH3:32])[C:22]=4[CH:33]=3)[C:14](=[O:34])[CH:13]=2)=[CH:8][CH:7]=1>C1COCC1>[O:27]1[CH2:30][CH2:29][N:28]=[C:26]1[C:24]1[N:23]([CH3:32])[C:22]2[CH:33]=[C:18]([N:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]4[CH:8]=[CH:7][C:6]([F:5])=[CH:36][CH:35]=4)=[CH:13][C:14]3=[O:34])[CH:19]=[CH:20][C:21]=2[N:25]=1
Reactant: Cn1c(C(=O)NCCO)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1c(C2=NCCO2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
Thionyl chloride (0.078 ml) was added to a mixture of 6-(4-((4-fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-(2-hydroxyethyl)-1-methyl-1H-benzimidazole-2-carboxamide (50.0 mg) in THF (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h, and at 50° C. under Ar atmosphere for 2 h. After evaporation of the solvent, THF (2 ml) was added to the residue. NaH (40% oil dispersion, 34.3 mg) was added to the mixture at 0° C. The mixture was stirred at room temperature for 1 h, and at 50° C. under Ar atmosphere for 2 h. After addition of water (0.5 ml), the mixture was stirred at room temperature over weekend. The mixture was quenched with brine and extracted with EtOAc/THF. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The solid was washed with EtOAc to give the title compound (17.9 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH2:5]2.[Br:14]C1C=CC2C(=CC=CC=2)C=1Br.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:14][CH:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]1
Reactant: Brc1ccc2ccccc2c1Br
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Product: CC1(C)CCC(Br)c2cc(Br)ccc21

Procedure:
Employing the above-described procedure for the conversion of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) to the dibromonaphthalene derivative (Compond I), 3.5 g (14.6 mmol) of (Compound F), 2.86 g (16.1 mmol) of N-bromosuccinimide and 150 mg (0.62 mmol) of benzoylperoxide gave crude 4,6-dibromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound I). To a solution of this crude dibromonaphthalene derivative (Compound I) in 50 ml of THF was added 5.38 g (47.1 mmol) of potassium thioacetate. The mixture was refluxed for 6 hours under argon atmosphere, filtered through celite and concentrated in vacuo. Purification by chromatography (silica, 10% EtOAc-hexane) yielded the title compound as red oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.Br[C:21]1[C:26]([F:27])=[C:25]([N+:28]([O-:30])=[O:29])[CH:24]=[CH:23][C:22]=1[F:31]>O1CCOCC1.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>[F:27][C:26]1[C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=[C:22]([F:31])[C:21]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Temperature: 150 °C
Yield: 33.9 %

Procedure:
2-Tributylstannanylpyridine (4.24 g, 12 mmol), 2-bromo-1,3-difluoro-4-nitrobenzene (2.5 g, 10 mmol) and Pd(PPh3)4 (605 mg, 0.5 mmol) in dioxane (20 mL) were placed in a microwave vial. The sealed vial was evacuated and purged with argon (×3). The resulting mixture was heated, under microwave irradiation, at 150° C. for 1.5 h. The cooled mixture was evaporated, and the residue was suspended in DCM and the resulting mixture filtered to remove insoluble material. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a bright orange solid (0.8 g, 33%). 1H NMR (CDCl3, 400 MHz): δ 8.79 (1H, ddd, J=6.5, 2.4, 1.3 Hz), 8.18 (1H, ddd, J=12.4, 10.8, 7.4 Hz), 7.86 (1H, td, J=10.4, 2.4 Hz), 7.51 (1H, dquin, J=10.5, 1.6 Hz), 7.41 (1H, ddd, J=10.2, 6.5, 1.5 Hz), 7.16 (1H, ddd, J=13.3, 10.8, 2.5 Hz)
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7]1)C.[OH-].[K+]>CO.CO.O>[CH3:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([OH:16])=[O:3])[CH:7]=1
Reactant: CCOC(=O)Cn1cc(C)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The residue, 3-methyl-indole-1-acetic acid ethyl ester, is dissolved in 900 ml of methanol, potassium hydroxide (90 g) in 400 ml of 1:1 methanol-H2O is then added. The mixture is stirred at room temperature for 11/2 hours. The methanol is evaporated under reduced pressure. The residue is diluted with water (800 ml) and extracted (3x) with ether. Acidification with 6NHCl of the aqueous phase yields 3-methyl-indole-1-acetic acid, m.p. 174°-176°C.