Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)=[O:31])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]([C:23]([OH:25])=[O:24])[CH2:8][NH:9][C:10]([C:12]1[C:13](O)=[N:14]C2C(N=1)=CC=CC=2)=[O:11])=[O:5].ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1OC2C=CC=CC=2C(=O)C=1)=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1C(=O)OC2C=CC=CC=2C=1)=O)=O.C1C2C(=CC3C(C=2C(NC[C@@H](C(O)=O)NC(=O)C2C=CC(C(NCC4C=CC=C(O)C=4)=O)=CC=2Cl)=O)=CC=CC=3)C=CC=1.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1[C:176]2[C:181]([N:182]=C3C=1CCCC3)=[CH:180][CH:179]=[CH:178][CH:177]=2)=O)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(C1C=CC2C(=O)C3C(SC=2C=1)=CC=CC=3)=O)=O>>[Cl:1][C:2]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)=[O:31])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]([C:23]([OH:25])=[O:24])[CH2:8][NH:9][C:10]([C:12]1[C:176]2[C:181](=[CH:180][CH:179]=[CH:178][CH:177]=2)[N:182]=[N:14][CH:13]=1)=[O:11])=[O:5]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2c3c(nc4ccccc24)CCCC3)C(=O)O)c(Cl)c1
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2nc3ccccc3nc2O)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2c3ccccc3cc3ccccc23)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc(=O)c3ccccc3o2)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc3ccccc3oc2=O)C(=O)O)c(Cl)c1
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cnnc3ccccc23)C(=O)O)c(Cl)c1

Procedure:
N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2-hydroxyquinoxaline-3-carbonyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(4-oxo-4H-1-benzopyran-2-carbonyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2-oxo-2H-1-benzopyran-3-carbonyl)amino-L-alanine; 3-(anthracene-9-carbonyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(1,2,3 ,4-tetrahydroacridine-9-carbonyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2-methoxy-11-oxo-11H-pyrido[2,1]quinazoline-8-carbonyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(9-oxo-9H-thioxanthene-3-carbonyl)amino-L-alanine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 58.4 %

Procedure:
A solution of 28 mg (0.12 mmol) of 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 19 mg (0.13 mmol) of 1-methyl-1,2,3,4-tetrahydro-isoquinoline, 23 mg (0.12 mmol) of EDC and 19 mg (0.12 mmol) of HOBt in 2 mL of DMF is stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the solid residue is partitioned between methylene chloride (3 mL) and saturated aqueous sodium hydrocarbonate solution (3 mL). The organic layer is separated, washed with 0.5 N HCl, water and brine and concentrated in vacuo. Purification of the residue by flash column chromatography (chloroform:methanol 99:1) gives 26 mg (58%) of title compound as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:38])([CH3:37])[C@@H:26]([OH:39])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16].[CH3:48][C:49]1([CH3:56])[CH2:54][C:53](=[O:55])[O:52][C:50]1=[O:51]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][C:2]1([CH3:47])[C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@@H:3]1[NH:14][C:15]([C@:17]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:18]1[C@@H:19]1[C@@:32]([CH3:35])([CH2:33][CH2:34]2)[C@@:31]2([CH3:36])[C@@H:22]([C@:23]3([CH3:40])[C@@H:28]([CH2:29][CH2:30]2)[C:27]([CH3:37])([CH3:38])[C@@H:26]([O:39][C:53](=[O:55])[CH2:54][C:49]([CH3:56])([CH3:48])[C:50]([OH:52])=[O:51])[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)=[O:16]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 46.8 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1S,3R)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 8, 0.250 g, 0.385 mmol) 2,2-Dimethylsuccinic anhydride (0.26 ml, 2.31 mmol) and DMAP (0.094 g, 0.77 mmol) in pyridine (10 ml) were added at room temperature then the reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with EtOAc, the organic layer was washed with water, 1N HCl, water, brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200, elution 35% EtOAc in hexane) to afford the title compound as a off white solid. Wt: 0.140 g: Yield: 46.8%; 1H NMR. (300 MHz, CDCl3): δ 5.95 (d, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.52-4.43 (m, 1H), 4.19-4.09 (m, 1H), 3.82-3.40 (m, 8H), 3.17-3.04 (m, 1H), 2.92-1.82 (m, 1H), 2.71-2.29 (m, 6H), 2.00-1.91 (m, 3H), 1.80-1.09 (m, 28H), 1.00-0.77 (m, 21H); Mass: [M+1]+ 779 (100%), [M+Na]+ 801 (15%); IR (KBr, cm−1): 3419, 2952, 2867, 1757, 1733, 1729, 1638, 1631, 1460, 1452, 1376, 1243, 1180, 1117, 1067, 978, 879, 775; M.R: 248.7° C.-252.6° C.; HPLC: 87.7%
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2F)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(F)c(CC2(O)CCN(Cc3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a suspension of NaH (55% in mineral oil, 200 mg, 5 mmol) in toluene (10 mL) was slowly added a solution of crude 1-benzyl-4-(2-fluoro-5-methylbenzyl)piperidin-4-ol in toluene (15 mL). After addition was completed, the reaction mixture was heated to 110° C. and stirred for 5 min. DMF (9 mL) was added and stirring was continued at reflux temperature for 10 h. The reaction mixture was cooled to room temperature, poured into water (50 ml), and extracted with ethyl acetate (2×25 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (ethyl acetate/n-heptane) to give the subtitle compound (240 mg, 41%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=O)[CH2:21]2)=[CH:16][CH:15]=1.C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C.C(O)(C)C.C(OCC)C>[ClH:11].[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH:20]([NH:1][CH2:2][CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=3)[OH:4])[CH2:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc2c(c1)CC(NCC(O)c1cccc(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of 4.8 g of 2-amino-1-(3-chlorophenyl)ethanol and 5 g of 7-methoxy-2-tetralone in 80 ml of methanol and 5 ml of glacial acetic acid is stirred at room temperature for three hours. Then 2.7 g of sodium cyanoborohydride are added thereto and the solution thus obtained is left under stirring for a night. The mixture is made acid and evaporated to dryness, then the residue is taken up with 40 ml of water made alkaline and extracted with 200 ml of ethyl acetate. The organic phase thus obtained is dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oil thus obtained is purified by flash-chromatography using a mixture ethyl acetate/methanol 95/5 for the elution. To the solution thus obtained there is added 40 ml of isopropyl alcohol and 150 ml of ethyl ether, then some drops of isopropyl alcohol saturated with hydrogen chloride. Thus, there is obtained the 2-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chloropheny)ethanol hydrochloride, designated by its code number SR 58338 A, which, after crystillization from isopropyl alcohol, melts at 186°-188° C. Yield: 40% of the theoretical value.
Reaction SMILES: [NH3:1].CO.[CH3:4][S:5][C:6]1[N:7]=[N:8][C:9]([C:23]([O:25]CC)=O)=[C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[N:11]=1>C1COCC1>[CH3:4][S:5][C:6]1[N:7]=[N:8][C:9]([C:23]([NH2:1])=[O:25])=[C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[N:11]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Nc1ccc2ncccc2c1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CSc1nnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A 2 M ammonia-methanol solution (3 ml) was added to a solution of ethyl 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (150 mg) in THF (0.5 ml), and then the reaction solution was stirred in a microwave reactor at 130° C. for 30 minutes. The precipitate was filtrated to obtain 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxamide as a crude white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][CH:11]([Cl:15])[C:12](Cl)=[O:13]>C(N(CC)CC)C>[Cl:10][CH:11]([Cl:15])[C:12]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)=[O:13]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1cccc(C=O)c1
Solvent: CCN(CC)CC
Product: O=Cc1cccc(NC(=O)C(Cl)Cl)c1

Procedure:
3-Aminobenzaldehyde can be treated with dichloroacetyl chloride and triethylamine to yield 2,2-dichloro-N-(3-formylphenyl)acetamide.
Reaction SMILES: N1(C2C=CC([C:13]3[NH:21][C:16]4=NC=CN=[C:15]4[C:14]=3[CH2:22][CH2:23][C:24]([NH:26]C)=O)=CC=2)CCOCC1.[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1>[C:28]1([C:22]2[CH:23]=[CH:24][N:26]=[C:13]3[NH:21][CH:16]=[CH:15][C:14]=23)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CNC(=O)CCc1c(-c2ccc(N3CCOCC3)cc2)[nH]c2nccnc12
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2ccnc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 1-(2,6-dimethyl-1,4-dihydropyridin-4-one)-1H-pyrrolo[2,3-b]pyridinium tetrafluoroborate (Reference Example 43, 1.0 g) in tetrahydrofuran (100 mL) was treated with a solution of phenylmagnesium bromide in tetrahydrofuran (9.6 mL, 1M) and stirred at room temperature for 72 hours before adding water ((100 mL) and the tetrahydrofuran removed in vacuo. The residue was extracted with chloroform (3×100 mL), and the combined organics dried over sodium sulfate and evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (99:1 v/v) to give the title compound (83 mg) as a white solid. MS: 195 (MH+). 1H NMR [(CD3)2SO]: δ 8.27 (1H, d, J=4.1 Hz); 7.78 (2H, d, J=8.2 Hz); 7.57 (3H, m); 7.48 (1H, t, J=8.2 Hz); 7.19 (1H, d, J=3.5 Hz); 6.60 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)\[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)\[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Reaction time: 3 h
Yield: 68.5 %

Procedure:
In 50 ml of methanol, was dissolved 2.9 g (0.01 mole) of (E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (melting point 108°-109° C.) characterized by the NMR spectrum given below. To the solution was added 0.38 g (0.01 mole) of sodium borohydride, while keeping the temperature of the reaction system at 20° C. or below by cooling in ice. To the solution, after having been kept at 20° C. for 3 hours, was added 1 ml of acetic acid to effect decomposition. The organic layer was extracted with 100 ml of ethyl acetate and the extract was washed with 50 ml of a 5% aqueous hydrogencarbonate solution, and dried over anhydrous sodium sulfate. After the removal of the solvent by distillation under reduced pressure, the residue was recrystallized from n-hexane to obtain 2.0 g (69% yield) of the captioned compound having a melting point of 153°-155° C. The elementary analysis and NMR spectrum (determined on a solution in deuterochloroform and expressed in terms of δ value) of each compound were as shown below:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][C@@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:17]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[O:28][CH3:29]>C(O)C.O.Cl>[CH3:29][O:28][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=1[NH:18][C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][C@@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:17]=1)[C:23]([OH:25])=[O:24]
Reactant: CN1C(=O)C[C@H]2CCCN2c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N1CCC[C@@H]1CC(=O)N2C

Procedure:
A mixture of 0.15 g (0.0006 mole) of (R)-9-chloro-6-methyl-2,3,3a,4-tetrahydro-1H,6H-6,8,10,10b-tetraaza-benzo[e]azulen-5-one (VII-102) and 0.11 g (0.00066 mole) of 4-amino-3-methoxy-benzoic acid (Aldrich) in 15 mL of ethanol-water-hydrochloric acid (20:80:1) was heated by microwave at 160 degrees for 40 minutes, and then concentrated under reduced pressure. The residue was lyophilized to give crude 3-methoxy-4-((R)-6-methyl-5-oxo-2,3,3a,4,5,6-hexahydro-1H-6,8,10,10b-tetraaza-benzo[e]azulen-9-ylamino)-benzoic acid (I-102a) as a light yellow solid which was used without further purification in subsequent steps.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](Cl)=[O:39])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([NH:1][C:2]2[S:3][C:4]3[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH2:8][CH2:9][C:10]=3[N:11]=2)=[O:39])=[CH:32][CH:31]=1
Reactant: Nc1nc2c(s1)CCN(CC=Cc1cccnc1)CC2
Reactant: COc1ccc(CCC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)Nc2nc3c(s2)CCN(CC=Cc2cccnc2)CC3)cc1
Reaction time: 3 h

Procedure:
To a stirred mixture of 1.0 g (3.5 mmol) of 2-amino-6-(3-(3-pyridyl)allyl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine and 0.53 ml (3.8 mmol) of triethylamine in 40 ml of anhydrous chloroform, there is added dropwise at ambient temperature a solution of 3- (4-methoxy-phenyl)-propionyl chloride (bp: 150° C./15 torr) in 7 ml of chloroform. The mixture is stirred for 3 hours at 60°-70° C., cooled and extracted with water. The dried and filtered chloroform solution is evaporated down in vacuo and the evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=5:1). Yield: 0.74 g (47% of theory), Melting point: 168°-170° C. (ether).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[Br:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]nc(Br)c2c1

Procedure:
A solution of 1H-Indazole-5-carbaldehyde (2.05 mmol) and N-bromosuccinimide (3.08 mmol) in DMF (8 mL) was stirred at rt for 3 h, then concentrated under reduced pressure. Chromatographic purification of the residue (silica gel, hexanes to hexanes:EtOAc, 1:1) afforded 3-bromo-1H-indazole-5-carbaldehyde as pale yellow solid.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:20]([C:21]#[N:22])=[C:19]([N:23]=[CH:24]OCC)[NH:18][N:17]=2)=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>C(O)C>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:20]3[C:21](=[NH:22])[N:32]([C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([Cl:28])[CH:30]=4)[CH:24]=[N:23][C:19]=3[NH:18][N:17]=2)=[CH:13][CH:14]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC=Nc1[nH]nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c1C#N
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 7 g (18.9 mmol) of 3-[4-(N-BOC-amino)-phenylamino]-4-cyano-5-(ethoxy-methyleneamino)-pyrazole, 3.97 ml (37.78 mmol) of 3-chloro-aniline and 150 ml of ethanol is heated under reflux for 9 hours and stirred at room temperature for a further 15 hours. Filtering and washing the filter residue with cold ethanol yield the title compound; m.p. 229-234° C. (decomp.); FAB-MS: (M+H)+ =452.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[CH2:29][S:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH:6]=1.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[CH2:29][S:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#C[Si](C)(C)C)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1

Procedure:
{3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester (0.920 g, 1.63 mmol), (trimethylsilyl)acetylene (0.34 mL, 2.45 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.1155, 0.16 mmol), and copper iodide (0.031 g, 0.16 mmol) were combined in triethylamine (8 mL) and degassed for 5 minutes. The reaction was heated for 8 hours, and then worked-up with CH2Cl2 and H2O. The crude material was purified by silica gel chromatography to give {3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trimethylsilanylethynyl-phenyl}-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:39]=[C:38]([NH:40][C:41]([C:43]2[C:44](=[O:56])[N:45]([C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[N:46]=[CH:47][CH:48]=2)=[O:42])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11](CC3C=CC(OC)=CC=3)[N:12]=[C:13]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:6]=12.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:39]=[C:38]([NH:40][C:41]([C:43]2[C:44](=[O:56])[N:45]([C:49]3[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=3)[N:46]=[CH:47][CH:48]=2)=[O:42])[CH:37]=[CH:36][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][N:12]=[C:13]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:6]=12
Reactant: COc1ccc(Cn2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(C4CCNCC4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A 50 mL round-bottomed flask was charged with tert-butyl 4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-1-carboxylate (30.0 mg, 0.0393 mmol) (Example 105, step D) and CF3COOH (5 mL). The reaction mixture was stirred at 80° C. overnight. Then the solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (19.5 mg, 91.3%). LRMS (APCI pos): >99% purity, 254 nm, m/e 544 (M+1). 1H NMR (400 MHz, CDCl3+CD3OD, 50/50, v/v) δ 11.94 (s, 1H), 8.42 (m, 1H), 8.28 (m, 2H), 8.00 (m, 1H), 7.62 (m, 2H), 7.46 (m, 1H), 7.35 (m, 1H), 7.24-7.32 (m, 2H), 6.16 (d, 1H), 3.64 (m, 1H), 3.50 (m, 2H), 3.14 (m, 2H), 2.38 (m, 2H), 2.25 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:15]1([CH:21]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:22][N:23]([CH2:36][CH2:37][CH2:38]O)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=2[Cl:35])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.OC1C=C(C=CC=1)CC1N(COCC)N=NN=1.BrCCCO.[CH3:68][S:69]([OH:72])(=[O:71])=[O:70]>ClCCl>[S:69]([OH:72])(=[O:71])(=[O:70])[CH3:68].[S:69]([OH:72])(=[O:71])(=[O:70])[CH3:68].[Cl:35][C:26]1[C:27]([C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:23]([CH2:22][CH:21]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:36][CH2:37][CH2:38][O:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[N:13]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: CN1CCN(c2cccc(O)n2)CC1
Agent: CCOCn1nnnc1Cc1cccc(O)c1
Agent: CS(=O)(=O)O
Agent: OCCCBr
Solvent: ClCCl
Product: CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)n2)CC1

Procedure:
Following the procedure of Example 6(d), except 6-(4-methyl-piperazin-1-yl)-pyridin-2-ol and N-(2,2-Diphenylethyl)-N-(3-hydroxy-propyl)-N-(2-chloro-3-trifluoromethyl-benzyl)amine were used instead of 5-(3-hydroxy-benzyl)-ethoxymethyl-1,2,3,4-tetrazole and 3-bromo-propanol in step 6(d), the title compound was synthesized as the free base. The tertiaryamine was then dissolved in dichloromethane and two equivalents of methanesulfonic acid were added to afford the title compound as the dimesylate salt, 47 mg (19% yield), as a white solid. MS (ESI) 623.4 (M+).
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4[CH2:29]COC[CH2:25]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.Cl.[C:39](N)(C)(C)C>>[C:24]([NH:23][C:21]([C:15]1[N:11]2[CH2:12][CH2:13][O:14][C:8]3[CH:7]=[CH:6][C:5]([C:4]#[C:3][C@@:2]([OH:1])([C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[CH3:31])=[CH:30][C:9]=3[C:10]2=[N:17][C:16]=1[C:18]([NH2:20])=[O:19])=[O:22])([CH3:25])([CH3:29])[CH3:39]
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Reactant: CC(C)(C)N
Agent: Cl
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC(C)(C)C)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing oxan-4-amine hydrochloride with tert-butylamine hydrochloride, off-white solid (58.7 mg, 25%).