Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[S:18][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]2=[O:25])=[CH:9][C:8]=1[O:26][CH3:27].CN(C=O)C.[O:43]([C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[S:53])=[CH:47][CH:46]=1)[CH3:44]>CC#N>[CH3:44][O:43][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([N:22]2[CH2:21][CH2:20][N:19]([C:17]3[S:18][C:14](=[CH:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]5[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:3]=5[C:2]([F:36])([F:1])[F:37])=[C:8]([O:26][CH3:27])[CH:9]=4)[C:15](=[O:25])[N:16]=3)[CH2:24][CH2:23]2)=[S:53])=[CH:47][CH:46]=1
Reactant: COc1cc(C=C2SC(N3CCNCC3)=NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: COc1ccc(N=C=S)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(NC(=S)N2CCN(C3=NC(=O)C(=Cc4ccc(OCc5ccc(C(F)(F)F)cc5C(F)(F)F)c(OC)c4)S3)CC2)cc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
To a N2 purged flask was added 5-[1-[4-(2,4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-methylidene]-2-piperazin-1-yl-thiazol-4-one (120 mg, 220 μmol) from Example 23, DMF (8 mL) and MeCN (8 mL). To the reaction solution was added 4-methoxylphenyl isothiocyanate (55 mg, 330 μmol). The reaction was stirred at 55° C. for 20 h and LC analysis should product was formed. The reaction solution was concentrated under reduced pressure and then taken into EtOAc (100 mL), washed with aq. NH4Cl (70 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed using reverse phase preparative HPLC, H2O/MeCN gradient 90:10 to 10:90) to provide the title compound as a white solid (24 mg, 13% yield). 1H NMR (DMSO-d6) δ 8.17 (1H, d, J=8.1 Hz), 8.11 (1H, s), 8.02 (1H, d, J=8.1 Hz), 7.64 (1H, s), 7.15-7.23 (5H, m), 6.88 (2H, d, J=8.9 Hz), 5.42 (2H, s), 4.16 (2H, br s), 4.09 (2H, m), 4.03 (2H, m), 3.86 (3H, s), 3.80 (2H, m), 3.74 (3H, s); MS (ESI) 711 (MH+).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:32]C(=O)OC(C)(C)C)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23](C3CN(C)CCC=3)[S:24][C:17]=12>>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:16]3[CH2:17][CH2:18][N:19]([CH3:20])[CH2:1][CH:3]=3)[S:24][C:17]=12)[NH2:32]
Reactant: O=C(O)C(F)(F)F
Reactant: CN1CCC=C(c2cc3nccc(Oc4ccc(NC(=O)OC(C)(C)C)cc4F)c3s2)C1
Product: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
TFA (1 mL) was added to tert-butyl 3-fluoro-4-(2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate (229) (105 mg, 0.23 mmol) and the mixture was stirred for 1 h at room temperature. The solution was concentrated under reduced pressure, the residue co-distilled with MeCN, redissolved in MeOH and purified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) giving 230 (50 mg, 0.1 mmol, 48% yield) as a white solid. MS (m/z): (M+1) 356.1 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([NH:14][C@:15]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:16]2[C@@H:17]2[C@@:30]([CH3:33])([CH2:31][CH2:32]3)[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:47])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18]2)=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([NH:14][C@:15]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:16]2[C@@H:17]2[C@@:30]([CH3:33])([CH2:31][CH2:32]3)[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:47])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]3[CH:46]=[CH:45][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18]2)=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)C3(NC(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C3(NC(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (101 mg, 0.139 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (17.49 mg, 0.417 mmol) in water (1.000 mL). The resulting mixture was stirred at 75° C. After 18 h, the reaction mixture was concentrated. The residue was redissolved in THF/MeOH, silica gel (2 g) was added and the mixture was concentrated to dryness. The absorbed material was loaded onto a silica gel column (25 g cartridge) and eluted with 0% B (solvent B=(90:10 DCM:MeOH, A=100% DCM) to 50% B for 180 mL, then hold at 50% B for 900 mL. Thus was obtained 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(1-(tert-butoxycarbonylamino)cyclopropanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (39 mg, 0.054 mmol, 38.6% yield) as white solid. LCMS: m/e 713.6 (M+H)+, 2.32 min (method 1). 1H NMR (500 MHz, 1:1 CDCl3:METHANOL-d4) δ 7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 3H), 6.62 (br. s., 1H), 5.33-5.24 (m, 1H), 4.72 (s, 1H), 4.63 (s, 1H), 2.61-2.36 (m, 3H), 2.13 (dd, J=17.2, 6.3 Hz, 1H), 2.04-1.95 (m, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.41 (d, J=6.1 Hz, 2H), 1.26 (br. s., 9H), 1.15 (s, 3H), 1.10 (br. s., 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.88 (d, J=6.7 Hz, 2H), 0.86-0.83 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>[Fe].CCOCC>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([C:11]#[N:12])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1Br
Agent: [Fe]
Solvent: CCOCC
Product: N#Cc1ncc(N)cc1Br

Procedure:
3-Bromo-2-cyano-5-nitropyridine (0.4 g, 1.75 mmol) and iron powder (0.51 g, 8.8 mmol, 325 Mesh) were reacted as described in example 762D. The crude solid obtained by trituration with ether was purified by SiO2 Prep-TLC using 4:1 CH2Cl2/ether as eluent to give compound 769A (0.16 g, (65%) as an off-white solid. HPLC: 100% at 1.77 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 197.93 [M+H]+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][S:4][CH:3]=[C:2]1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>>[S:1]1[CH2:6][CH2:5][S:4][CH:3]=[C:2]1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=CSCCS1
Product: O=C(Cl)C1=CSCCS1

Procedure:
A suspension of 5,6-dihydro-1,4-dithiin-2-carboxylic acid (13.1 g) in thionyl chloride (60 cc) is gradually heated to reflux. After 30 minutes under reflux, the solution obtained is concentrated to dryness at 50° C. under reduced pressure (4 kPa) and the oily residue obtained is washed with cyclohexane (2×100 cc). The decanted oil is dried at 50° C. under reduced pressure (4 kPa). 5,6-Dihydro-1,4-dithiin-2-carbonyl chloride (15.8 g) is thereby obtained, and this is used as it is in the following operation.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].N1C=CC=CC=1.[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45](Cl)=[O:46])[N:44]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([Cl:17])=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])=[O:46])[N:44]=1
Reactant: CS(=O)(=O)Nc1cc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Reactant: O=C(Cl)c1csc(CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cnc1Cl
Temperature: 20 °C
Reaction time: 66 h
Yield: 30.9 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methanesulfonamide (780 mg, 1.632 mmol) was dissolved in DCM (32 ml) and pyridine (0.198 ml, 2.448 mmol) and cooled to 0° C. To this was added 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) dropwise. The reaction was left to warm up and after final addition was stirred for a further 66 h at 20° C. Reaction was incomplete so the mixture was cooled again to 0° C. and a further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) was added dropwise. The reaction was left to warm up and was stirred for a further 23 h at 20° C. Reaction still incomplete so, the mixture was cooled again to 0° C. and a further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (320 mg, 1.632 mmol) as a solution in DCM (6 ml) was added dropwise. The reaction was left to warm up and was stirred for a further 23 h at 20° C. The solution was treated with DCM (25 ml) and saturated aqueous sodium bicarbonate (25 ml) and stirred vigorously for 10 mins. The organic phase was then separated, washed with dilute aqueous sodium chloride (30 ml), passed through a hydrophobic frit, and loaded directly onto a 100 g silica cartridge. This was eluted with 0-100% ethyl acetate/cyclohexane over 60 mins using the Flashmaster II. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (321 mg).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[CH3:10][N:11]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[N:15]=[CH:14][C:13]2=[CH:22][CH:23]=[CH:24][N:12]12.[Cl-].[NH4+]>O1CCCC1>[CH3:10][N:11]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:16]=2[NH:15][CH:14]([CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[C:13]2=[CH:22][CH:23]=[CH:24][N:12]12
Reactant: CN1CCC(Cl)CC1
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2Nc3cnccc3N(C)n3cccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a warm Grignard reagent prepared from 7.2 g of 4-chloro-1-methyl piperidine and 1.4 g of magnesium metal in 50 ml of tetrahydrofuran was added a solution of 5.3 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 50 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 15 minutes, added to an iced ammonium chloride solution and extracted with ethyl acetate (3×). The combined organics were washed with water (2×) followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resultant solid was purified by means of high pressure liquid chromatography (silica gel; elution with 50% methanol/dichloromethane). Recrystallization from ethyl acetate:methanol (20:1) afforded 1.65 g of 10,11-dihydro-5-methyl-10-[(1-methyl)piperidin-4-yl]-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp: 235°-238° C. (dec.).
Reaction SMILES: [C:1]1([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[C:9]([F:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.[Na]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH:11][C:17]3[CH:22]=[CH:21][C:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[C:9]([F:15])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(F)c(-c2ccccc2)cc1F
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1ccc(Nc2cc(F)c(-c3ccccc3)cc2F)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
4-phenyl-2,5-difluoroaniline (12 mmol), 4-bromo-trimethylsilylbenzene (10 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.15 mmol), (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthalene (0.3 mmol) and sodium tert-butoxie (14 mmol) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 4-phenyl-2,5-difluoro-N-(4-trimethylsilylphenyl)benzenamine (2.6 g) is yielded.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[NH2:18])=[O:6])C.[Cl:19][CH2:20][C:21]#[N:22].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[Cl:19][CH2:20][C:21]1[NH:22][C:5](=[O:6])[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][S:9][C:8]=2[N:18]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: N#CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(CCl)nc2scc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.8 %

Procedure:
Hydrogen chloride gas was bubbled through a stirred solution of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (4.94 g, 0.02 mol) and chloroacetonitrile (1.4 ml, 0.022 mol) in anhydrous 1,4-dioxane (60 ml) for about 4 hours. A thick suspension formed initially which slowly dissolved. The mixture was stirred at ambient temperature for 18 hours before being poured into water (250 ml) and basified (pH 8) by the addition of sodium hydrogen carbonate. The supernatant was then decanted to leave a gummy solid which was triturated with aqueous ethanol to give 2-chloromethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid (3.70 g), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C.C(OCC)(=O)C>[CH:20]1([CH2:19][O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)c(F)c1
Temperature: 70 °C

Procedure:
To a solution of 2-fluoro-4-nitrophenol (10.0 g) in DMF (100 mL) were added potassium carbonate (17.6 g) and (bromomethyl)cyclopropane (9.26 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated to give the title compound (13.8 g).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.Cl.Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[CH:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28](/[CH:33]=[CH:34]/[C:35]3[CH:36]=[N:37][C:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)=[CH:39][CH:40]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C@:16]12[CH2:4][C@H:23]1[C:24]1[CH:32]=[C:31]2[C:27]([C:28](/[CH:33]=[CH:34]/[C:35]3[CH:36]=[N:37][C:38]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)=[CH:39][CH:40]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1
Reactant: C[S+](C)(C)=O
Reactant: COc1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(/C=C/c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (3 mL) was added to a mixture of NaH (60%, 171.5 mg, 4.29 mmol) and trimethylsulfoxonium iodide (246.2 mg, 1.12 mmol). The resulting mixture was stirred at rt for 10 min followed by the addition of 5-methoxy-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one dihydrochloride (E:Z mixture, 155.5 mg, 0.275 mmol) as a suspension in DMF (9 mL, divided for transfer and vial rinse). The reaction mixture was then heated to 55° C. for 6 h, then stirred at rt for 18 h prior to quenching by addition of water (15 mL) and brine (15 mL). The mixture was extracted with EtOAc (225 mL) and the organic layer was washed with brine (2×15 mL), dried over Na2SO4 and concentrated in vacuo. Co-evaporation of DMF with toluene (2×10 mL) in vacuo gave a viscous oil, which was triturated with hexane (3×5 mL) to give a sticky solid. The crude product was purified by silica gel chromatography (5-7.5% 2M NH3-MeOH in DCM) to yield an 85:15 mixture of the title compound and the (1R*,2R*) diastereomer. The major isomer was isolated by silica gel chromatography (3-5% MeOH and 2% Et3N in CHCl3) to yield a sticky yellow solid which was triturated with Et2O to give the title compound as a yellow powder (57.4 mg, 41%). 1H NMR (400 MHz, CD3OD) δ ppm 8.26 (s, 1 H), 8.00 (d, J=8.4 Hz, 1 H), 7.92 (d, J=9.2 Hz, 1 H), 7.45 (s, 1 H), 7.40 (d, J=16.8 Hz, 1 H), 7.28 (d, J=16.8 Hz, 1 H), 7.03 (d, J=7.6 Hz, 1 H), 6.87 (d, J=9.2 Hz, 1 H), 6.83 (d, J=8.4 Hz, 1 H), 6.61 (dd, J=8.4, 2.4 Hz, 1 H), 5.58 (d, J=2.0 Hz, 1 H), 3.61 (m, 4 H), 3.38 (m, 1 H), 3.26 (s, 3 H), 2.57 (m, 4 H), 2.36 (s, 3 H), 2.21 (m, 2 H); MS ESI [M+H]+ 507.2, calcd for [C30H30N6O2+H]+ 507.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:15](=[CH:21]O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH2:24].C1COCC1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][N:24]([CH3:23])[C:10](=[O:11])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)C=C(C(=CO)C(=O)OCC)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cn(C)c(=O)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
A mixture of Example 41B (1.50 g, 4.62 mmol), 2M methylamine in THF (3.5 mL, 7.0 mmol), and acetic acid (1.5 mL) in ethanol (20 mL) was heated to reflux for 30 minutes, cooled to room temperature, and concentrated. The concentrate was dissolved in acetonitrile (15 mL), treated with K2CO3 (3.2 g, 23.0 mmol), stirred for 18 hours, and concentrated. The concentrate was dissolved in dichloromethane, washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 19:1 dichloromethane/acetone to provide 586 mg (41%) of the desired product. MS (DCI/NH3) m/z 292 (M+H)+; 1H NMR (CDCl3) δ 8.22 (s, 1H), 7.35 (m, 2H), 7.23 (m, 1H), 7.12 (m, 1H), 6.43 (s, 1H), 4.09 (q, 2H), 3.65 (s, 3H), 1.04 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[OH:61][CH:62]1[CH2:65][NH:64][CH2:63]1>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22]([N:64]5[CH2:65][CH:62]([OH:61])[CH2:63]5)=[O:23])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: OC1CNC1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)N2CC(O)C2)ccc1Cl
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (2.5 g, 5.07 mmol) in THF (50 mL) was added EDCI (1.94 g, 10.14 mmol), HOBt (1.03 g, 7.61 mmol), DIPEA (5 mL) and 3-hydroxyazetidine hydrochloride (0.83 g, 7.61 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (eluted by hexanes: EtOAc=1:2) to give 8-bromo-N-(2-chloro-5-(3-hydroxyazetidine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (1.6 g, yield 58%). LC-MS: (ESI, m/z)=547 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.P(Cl)(Cl)Cl.[NH2:19][C:20]1[S:21][C:22]([C:25]2[S:26][C:27]([Br:30])=[CH:28][CH:29]=2)=[CH:23][N:24]=1>O>[Br:30][C:27]1[S:26][C:25]([C:22]2[S:21][C:20]([NH:19][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:24][CH:23]=2)=[CH:29][CH:28]=1
Reactant: Nc1ncc(-c2ccc(Br)s2)s1
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ncc(-c2ccc(Br)s2)s1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.43 g) of Preparation 1 in 80 mL xylenes is heated to reflux. PCl3 (0.12 mL) is added dropwise and the mixture stirred for 20 minutes. 2-Amino-5-(5-bromothien-2-yl)thiazole (0.62 g) is added in one portion and the reaction refluxed overnight. The reaction is cooled to room temperature and H2O is added to quench excess PCl3. The solvents are removed and the residue is dissolved in acetic acid. A dark orange solid precipitates upon addition of hexanes (0.28 g) to yield the title product.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:10](N)=[O:11]>>[CH:10]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:11]
Reactant: NC=O
Reactant: CC(C)C[C@H](N)C(=O)O
Product: CC(C)C[C@H](NC=O)C(=O)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
165.2 g of L-leucine and 821.7 g of formamide are introduced, under a nitrogen atmosphere, into a reactor equipped with a stirrer system. The mixture is heated at 100° C. for approximately 6 hours. Approximately 513 g of formamide are then removed by distillation under a pressure of 20 -30 mm of mercury and at a pot temperature of 50°-60° C. 1082 g of water are subsequently added to the mixture. It is cooled to 20°-25° C. It is then acidified to pH 2.5 with sulphuric acid. It is stirred for 2 hours at approximately 20° C. and then for one hour at 5° C. Filtration is carried out and the cake is rinsed with 100 g of water at pH 2. It is dried under vacuum. 180.3 g of N-formyl-L-leucine are thus obtained (90% yield) with an optical rotation [α]D20=−17.7° (c=1 in ethanol), i.e. a purity of 98.3%.