Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([NH:10][C:11]2([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:30][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=2)[C@@H:4]([C:8]([NH:10][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[CH2:12][CH2:13]2)=[O:9])[CH2:3]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)CCN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D134) (26 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-((2R)-4-fluoropiperidine-2-carboxamido)cyclopropyl)benzoate (D96) (39 mg) and 4-(trifluoromethyl)-benzylbromide (0.015 ml). (Cs2CO3: 1.3 eq; reaction time: 18 hrs; RT).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li][CH2:17][CH2:18][CH2:19][CH3:20].[Br:21][C:22]1[CH:23]=[C:24]2[C:42](=[CH:43][CH:44]=1)[C:27]1=[CH:28][C:29]3[C:30](=[O:41])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[C:37](=[O:40])[C:38]=3[CH:39]=[C:26]1[C:25]2([CH3:46])[CH3:45]>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]2[C:42](=[CH:43][CH:44]=1)[C:27]1=[CH:28][C:29]3[C:30]([C:18]4[C:19]5[C:20]([C:2]6[CH:15]=[CH:14][CH:9]=[CH:8][C:3]=6[CH:17]=4)=[CH:7][CH:6]=[CH:5][CH:4]=5)([OH:41])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[C:37]([C:2]4[C:3]5[C:8]([C:9]6[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=6[CH:15]=4)=[CH:7][CH:6]=[CH:5][CH:4]=5)([OH:40])[C:38]=3[CH:39]=[C:26]1[C:25]2([CH3:46])[CH3:45]
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: [Li]CCCC
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1ccccc1C3=O
Solvent: C1CCOC1
Product: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(O)(c1cc2ccccc2c2ccccc12)c1ccccc1C3(O)c1cc2ccccc2c2ccccc12
Reaction time: 1 h
Yield: 71.8 %

Procedure:
9-bromophenanthrene (13.88 g, 0.054 mol) was placed in a flask, and THF (200 ml) was added thereto. After dissolution, n-BuLi (38.4 ml, 0.06 mol) was gradually added at −780, and the reaction mixture was stirred for one hour at a maintained temperature. Then, 2-bromo-13,13-dimethyl-6H-indeno[1,2-b]anthracene-6,11(13H)-dione (10 g, 0.024 mol) was added and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was terminated, the reaction solution was washed with distilled water, extracted with ethyl acetate, and purified by column chromatography to give, 2-bromo-13,13-dimethyl-6,11-di(phenanthren-9-yl)-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (13.1 g, yield=72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH2:23])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.O.[N:25]#[C:26][Br:27]>C(#N)C>[BrH:27].[NH2:25][C:26]1[NH:23][C:22]2[CH:21]=[CH:20][C:4]([O:5][CH2:6][CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:9][CH2:8]3)=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(N)c(N)c2)CC1
Reactant: N#CBr
Solvent: CC#N
Solvent: O
Product: Br
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
tert-Butyl 4-((3,4-diaminophenoxy)methyl)piperidine-1-carboxylate (10.18 mmoles, 3.27 g, 1 equivalent) was dissolved in acetonitrile (40 ml) and water (20 ml) and cooled to 0-5° C. (ice-water). Cyanogen bromide (1.112 g, 10.5 mmoles) was added in one lot and the reaction mixture was allowed to go to room temperature and stirred for 16 hours. The reaction mixture was then evaporated under reduced pressure to give 3.53 g of tert-butyl 4-((2-amino-1H-benzo[d]imidazol-5-yloxy)methyl)piperidine-1-carboxylate hydrobromide (yield n 100%) which was used directly in the next step without any further purification. 1H-NMR (400 MHz, DMSO-d6) δ 12.22 (br s, 2H), 8.30 (s, 2H), 7.21 (d, 1H), 6.90 (s, 1H), 6.79 (d, 1H), 3.96 (m, 2H), 3.82 (d, 2H), 2.73 (m, 2H), 1.91 (m, 1H), 1.74 (d, 2H), 1.39 (s, 9H), 1.26 (m, 2H). MS (EI): 347 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH2:29])[C:25]([NH2:28])=[CH:26][CH:27]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=[S:31]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]5[NH:28][C:30](=[S:31])[NH:29][C:24]=5[CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccc3c(c2)CN(c2ccnc4ccccc24)CCO3)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: S=c1[nH]c2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
To a solution of 4-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-benzene-1,2-diamine (630 mg, 1.65 mmol, synthesized according to the method of example 2 step) in tetrahydrofuran (30 mL) was added 1,1′-thiocarbonyldiimidazole (587 mg, 3.29 mmol), and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue crystallized from methanol to give 5-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-dihydro-2H-benzimidazole-2-thione (357 mg, 51% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6): 12.74 (s, 1H), 12.66 (s, 1H), 8.57 (d, 1H), 8.28 (d, 1H), 8.00 (d, 1H), 7.95 (m, 1H), 7.88 (d, 1H), 7.67 (m, 1H), 7.53 (dd, 1H), 7.49 (dd, 1H), 7.40 (s, 1H), 7.24 (d, 1H), 6.97 (m, 2H), 5.21 (s, 2H), 4.58 (m, 2H), 4.33 (m, 2H); MS (EI) for C25H20N4OS: 425 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[CH:22][C:23]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1

Procedure:
According to the procedure example A12A, except substituting 3-iodo-1H-indazole-6-carbaldehyde and 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2-yl)piperazine (67 mg, 0.22 mmol), the title compound was obtained as a beige solid (57 mg, 99%). 1H NMR (400 MHz, CD3OD) 8 ppm 10.11 (s, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.8, 2.3 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 3.83-3.78 (m, 4H), 3.01 (t, J=5.0 Hz, 4H), 2.67 (s, 3H); MS ESI 322.1 (100) [M+H]+, calcd for [C18H19N5O+H]+ 322.16.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[O:6].O.[OH-].[Li+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:6]
Reactant: COC(=O)CCCCCNC(=O)c1ccc(-c2ccccc2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)NCCCCCC(=O)O)ccc1-c1ccccc1
Yield: 99.6 %

Procedure:
The procedure of the step 2 in Example 80 was repeated except for using methyl 6-(3-methyl-4-phenyl-benzamido)hexanoate (195 mg, 0.574 mmol) instead of methyl 6-(3-bromo-2-methylbenzamido)hexanoate, and lithium hydroxide monohydrate (54 mg, 1.29 mmol) to obtain the title compound (186 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][CH3:16])[CH2:11][CH2:10]2)[N:5]=[N:4][C:3]=1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[C:32]([C:33]([OH:35])=O)=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C(Cl)[Cl:57]>O>[ClH:57].[C:21]([C:20]1[CH:23]=[CH:24][C:17]([C:3]2[N:4]=[N:5][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([N:15]([CH3:16])[C:33](=[O:35])[C:32]4[C:27]([C:26]([F:25])([F:37])[F:36])=[CH:28][CH:29]=[N:30][CH:31]=4)[CH2:11][CH2:10]3)=[C:7]([CH3:8])[C:2]=2[CH3:1])=[CH:18][CH:19]=1)#[N:22]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CNC1CCN(c2nnc(-c3ccc(C#N)cc3)c(C)c2C)CC1
Reactant: ClCCl
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(-c2ccc(C#N)cc2)nnc(N2CCC(N(C)C(=O)c3cnccc3C(F)(F)F)CC2)c1C
Product: Cl
Reaction time: 72 h
Yield: 49 %

Procedure:
Treat a solution of 4-(4,5-dimethyl-6-(4-(methylamino)piperidin-1-yl)pyridazin-3-yl)benzonitrile (102 mg, 0.32 mmol), 4-(trifluoromethyl)nicotinic acid (81 mg, 0.42 mmol), triethylamine (0.07 mL, 0.5 mmol) in CH2Cl2 (4 mL) with EDCI (99 mg, 0.52 mmol) and stir for 3 d. Pour the reaction mixture into H2O and extract with EtOAc. Wash the organic layer with H2O, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify by flash silica gel chromatography (gradient of 0 to 10% MeOH in CH2Cl2). Dissolve the free base in MeOH (2 mL) and add 1 M HCl in Et2O (0.5 mL). Concentrate to provide the title compound (82 mg, 49%). ES/MS m/z 495.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](S(C)(=O)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-methoxy-5-pyridineboronic acid in General Procedure A. Purification on silica yielded 227. NMR (CDCl3): 2.67-2.69 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.29-3.31 (m, 4H, 2×CH2), 3.86-3.89 (m, 6H, 3×CH2), 4.01-4.05 (m, 7H, 2×CH2+CH3), 6.80 (d, H, ArH, J=8.56 Hz), 7.30 (s, H, ArH), 8.57 (dd, H, ArH, J=8.64 Hz, 2.31 Hz), 9.23 (d, H, ArH, J=2.22 Hz). MS: (ESI+): MH+ 505.15
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:24]([Cl:28])(Cl)([Cl:26])[Cl:25]>>[Br:7][C:2]1([CH2:1][C:24]([Cl:28])([Cl:26])[Cl:25])[O:6][C:4](=[O:5])[CH2:3]1
Reactant: ClC(Cl)(Cl)Br
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=C1CC(=O)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C1CC(Br)(CC(Cl)(Cl)Cl)O1

Procedure:
A mixture of 25.2 parts of diketene, 62.7 parts of bromotrichloromethane and 1.5 parts of azobisisobutyronitrile dissolved in 978 parts of carbon tetrachloride was irradiated by UV light at room temperature (20°-25° C.) for 5 hours. The mixture was evaporated at the water pump and the product, 4-bromo-4-(2,2,2-trichloroethyl)-oxetan-2-one, was obtained as a yellow oil which crystallised on cooling. Recrystallisation of this material three times from light petroleum ether (b.p. 40°-60° C.) gave white needles m.p. 55°-56° C.
Reaction SMILES: [C:1]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:13]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(C1C2C(=CC=CC=2)N(CCCC(OCC)=O)C=1)(=O)CCCCCC>>[C:1]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12
Agent: CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12
Product: CCCCCCCCCC(=O)c1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 2 was repeated except that ethyl 4-(3-decanoyl-1-indolyl)butyrate obtained in Ex. 7 was used in place of ethyl 4-(3-heptanoyl-1-indolyl)butyrate to give 4-(3-decanoyl-1-indolyl)butyric acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH:10]=[CH2:11])=[CH:4][CH:3]=1.[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:28]2([F:35])[CH2:33][CH2:32][NH:31][CH2:30][CH:29]2[CH3:34])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:28]2([F:35])[CH2:33][CH2:32][N:31]([CH2:11][CH2:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[O:12])[CH2:30][CH:29]2[CH3:34])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1CNCCC1(F)c1cccc(OCc2ccccc2)c1
Reactant: C=CC(=O)Nc1ccc(Br)cc1
Agent: Cl
Product: CC1CN(CCC(=O)Nc2ccc(Br)cc2)CCC1(F)c1cccc(OCc2ccccc2)c1
Yield: 65 %

Procedure:
This material was synthesized by the reaction of N-(4-bromophenyl)acrylamide with 4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidine hydrochloride as described in Step 1 of Example 20. The desired compound was obtained as a light yellow solid in 65% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([OH:16])[C:13]([C:17]#[N:18])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:12]=[C:13]([C:17]#[N:18])[C:14]([O:16][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(O)c(C#N)c2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(OCc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 22.8 %

Procedure:
To a solution of 4-(3-cyano-4-methoxypyrrole-1-yl)benzoic acid ethyl ester (0.081 g) in dichloromethane (3 mL) was added boron tribromide (0.33 mL, 1 mol/L dichloromethane solution) under ice-cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water, and this mixture was extracted with diethyl ether. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/1) to give 4-(3-cyano-4-hydroxypyrrole-1-yl)benzoic acid ethyl ester (0.052 g). To a solution of 4-(3-cyano-4-hydroxypyrrole-1-yl)benzoic acid ethyl ester (0.052 g) in N,N-dimethylformamide (4 mL) were added benzylbromide (0.038 g) and cesium carbonate (0.13 g) at room temperature, and this mixture was stirred at 80° C. for 5 hours. To this reaction mixture was added water at room temperature, and the precipitated solid was collected by filtration, and washed with methanol (5 mL) to give the title compound (0.016 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)=[CH:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl.CN(C=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]2[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)CCNC2c1c[nH]c2ccccc12
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1c[nH]c2ccccc12
Reaction time: 48 h

Procedure:
To a solution of 1-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (16.3 mg, 66 μmol) in CH2Cl2 (0.5 mL) at RT was added 1-fluoro-4-isocyanatobenzene (10 μL, 66 μmol). The reaction was stirred 48 h, the suspension dissolved in DMF and purified by HPLC to give N-(4-fluorophenyl)-1-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 386 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11](=[O:13])[N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])[CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: Nc1ncc(-c2cccc(C(=O)O)c2)cc1C(=O)Nc1ccncc1
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with N-(methoxy-ethyl)-methyl-amine gives “A97”; method 1: HPLC/MS: 1.23 min, [M+H]=406;
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:39]3[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]3)[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: O[C@@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@@H](Nc2nc(N3CC[C@@H](O)C3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, (R)-pyrrolidin-3-ol was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give (R)-1-[4-((R)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-yl]-pyrrolidin-3-ol. MS: (ES+): 459
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17].O>Cl.C(O)C>[CH3:12][C:13]1[NH:10][C:7]2[C:8]([C:14]=1[CH2:15][CH2:16][CH3:17])=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2
Reactant: CCCCC(C)=O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCc1c(C)[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 200 ml 2-neck round bottom flask, equipped with a magnetic stirrer and a cold water condenser, 4-nitrophenylhydrazine was dissolved in 75 mL concentrated hydrochloric acid and stirred at room temperature for 15 minutes. A solution of 2-hexanone (5 mL) in ethanol (25 mL) was added slowly and the reaction flask was heated in an oil bath at 105° C. for 18 h. The mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with EtOAc. The organic layer washed with saturated sodium bicarbonate solution, water, and brine solutions and evaporated to dryness. The oily residue was absorbed on silica gel and purified by silica gel chromatography with 20% EtOAc in Hexane solution to give 2-methyl-5-nitro-3-propyl-1H-indole. This indole product was dissolved in trifluoroacetic acid (10 mL) and 1 pellet sodium borohydride (0.7 g) was added and the reaction was stirred at room temperature for 18 h. Water (10 mL) was carefully added and the reaction mixture was extracted twice with EtOAc (15 mL). The organic layer washed with brine and dried over MgSO4, and purified by flash column chromatography on silica gel eluted with 20% EtOAc in hexanes to give 280 mg of 2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.B#B>C(Cl)Cl.O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Agent: B#B
Agent: OCCCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: BrCCCCCCCCc1ccccc1

Procedure:
8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride. A solution of 8-phenylocatanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil. To 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-triimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [CH3:1][N:2](/[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:5]1\[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[S:9]\1)[CH3:3].[OH:21]O>C(O)(=O)C>[CH3:3][N:2](/[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:5]1\[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[S:9]\1=[O:21])[CH3:1]
Reactant: CN(C)/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: OO
Solvent: CC(=O)O
Product: CN(C)/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1

Procedure:
Prepared analogous to Example 1 from (E)-2-[(dimethylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one and perhydrol in glacial acetic acid.