Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][CH2:27][CH:28]([OH:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28](=[O:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:45][CH:46]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(OCC(O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(OCC(=O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A solution of 3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxy carbonyl)phenoxy]-2-propanol (2.08 g, 3.25 mmol) in dichloromethane (120 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (5.46 g, 12.9 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed with 10% aqueous sodium thiosulfate, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 95:5) gave 1.82 g (88%) of the title material as oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:21]=[CH:20][N:19]=[CH:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:26]([C:25]4[CH:24]=[CH:23][C:22]([N:17]5[CH:21]=[CH:20][N:19]=[CH:18]5)=[CH:29][CH:28]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(-n4ccnc4)cc3)nc(=O)c1-2
Temperature: 130 °C
Reaction time: 72 h
Yield: 94.4 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.18 g, 5.32 mmol), 4-(1-imidazolyl)benzaldehyde (1.37 g) and xylenes (8 ml) was warmed to 130° C. for 30 minutes, then to 160° C. for three days. The reaction mixture was cooled, and the product was collected by filtration and washed with Et2O to afford 1.88 g of 1-cyclopentyl-3-ethyl-6-[4-(1-imidazolyl)phenyl]pyrazolo [3,4-d]pyrimidin-4-one as the 6,7-saturated derivative. This derivative was mixed with ethanol (300 ml) and 30% H2O2 (3.0 ml) and refluxed overnight. Additional 30% H2O2 (3 ml) was added and the mixture was refluxed for 8 hours. An additional 10 ml of 30% H2 O2 was added and the mixture was refluxed overnight. Starting material was still present so an additional 10 ml of 30% H2O2 was added and the mixture was refluxed for 4 hours and then additional 30% H2O2 (10 ml) was added and the mixture was stirred for 1 hour, then was allowed to stand at room temperature overnight. The reaction mixture was stripped to a yellow liquid and purified by column chromatography on silica gel eluting with ethyl acetate (100%), then 5% methanol/ethyl acetate to afford 0.4 g of 1-cyclopentyl-3-ethyl-6-[4-(1-imidazolyl)phenyl]-pyrazolo-[3,4-d] pyrimidin-4-one 1/2 hydrate, m.p.>300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@H:27]([OH:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH3:41][S:42]([O:38][C@@H:27]1[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29][C@H:28]1[NH2:30])(=[O:44])=[O:43]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a solution of tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in CH2Cl2 was added TEA (4.0 equiv.) and MsCl (2.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo, the residue was dissolved in DMSO, purified by RP HPLC and the product fractions were lyophilized directly. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield (1R,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 31% yield. LC/MS (m/z)=535.2 (MH+), Rt=0.61 min.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:20][CH:19]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:38][CH:39]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxyimino]-4-phenylbutyrate (460 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxyimino]-4-phenylbutyric acid (443 mg, yield 99%) as colorless crystals. m.p. 106-107° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[Br:1][C:2]1[C:3]([C:12]([F:13])([F:15])[F:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[C:6]([CH3:11])=[CH:5]2
Reactant: BrCC1CC1
Reactant: Cc1cc2c(C(F)(F)F)c(Br)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(Br)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 5-bromo-2-methyl-4-(trifluoromethyl)-1H-indole and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 6.49 (s, 1H), 3.99 (d, J=6.4 Hz, 2H), 2.46 (s, 3H), 1.14 (m, 1H), 0.56 (m, 2H), 0.32 (m, 2H); MS (ES) m/z 332 (M+1, isotope for Br) and 334 (M+1, isotope for Br).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH2:30]1COC[CH2:31]1>C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O.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>[CH:30]([C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1)=[CH2:31]
Reactant: C1CCOC1
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
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: CCOC(C)=O
Product: C=Cc1cc([C@H](CC)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-bromo-pyridin-4-yl)-propyl]-amide (1.1 g, 2.42 mmol), vinylboranic anhydride pyridine complex (O'shea's reagent) (582 mg, 2.42 mmol), and tetrakistriphenylphosphinepalladium(0) (279 mg, 0.24 mmol) in THF (7 mL) and 20% aqueous sodium carbonate (2.5 mL) was warmed at 70° C. After 18 hours, the mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with saturated aqueous sodium bicarbonate (2×100 mL), dried with MgSO4, filtered, and concentrated. The mixture was purified by silica gel chromatography eluting with a gradient of 70-100% EtOAc in hexanes to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-vinyl-pyridin-4-yl)-propyl]-amide.
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])[O:7][CH3:8])[O:3][CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[NH:1][C:2](=[N:5][C:6]([O:7][CH3:8])=[O:9])[O:3][CH3:4])=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)N=C(N)OC
Solvent: ClCCl
Product: COC(=O)N=C(NC(=O)Nc1ccc(Cl)cc1)OC
Reaction time: 8 h

Procedure:
To 13 parts of this methyl N-(1-amino-1-methoxymethylene)carbamate, m.p. 36°-39.5° in 140 parts of methylene chloride is added 15 parts of 4-chlorophenyl isocyanate. The reaction mixture is stirred overnight and the solution filtered to give 10 parts of methyl 4-(4-chlorophenyl)-N-methoxycarbonylallophanimidate melting at 170° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>ClCCCl.CN(C=O)C.CC#N.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CC#N
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.6 %

Procedure:
To a suspension of 2-(3,4-dichlorophenyl)acetic acid (137 mg, 0.67 mmol) in DCE (2.0 mL) was added oxalyl chloride (908 μL, 1.82 mmol, 2.0M solution in CH2Cl2) (0.908 mL, 1.816 mmol) followed by one drop of DMF. The resulting reaction mixture was stirred at room temperature for 40 min and then concentrated in vacuo. To a solution of the crude residue in MeCN (4.0 mL) was added indoline-5-sulfonamide (120 mg, 0.61 mmol) and K2CO3 (167 mg, 1.21 mmol). The reaction mixture was stirred at room temperature for 1 h. Additional indoline-5-sulfonamide (40 mg, 0.20 mmol) was added, and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted with EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with 10% aq. LiCl solution and then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with CH2Cl2 to give the title compound (180 mg, 77%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 8.11 (d, J=8.4 Hz, 1H), 7.59 (m, 4H), 7.29 (dd, J=8.1, 2.0 Hz, 1H), 7.22 (s, 2H), 4.26 (t, J=8.5 Hz, 2H), 3.94 (s, 2H), 3.24 (t, J=8.5 Hz, 2H); MS(ESI+) m/z 385.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([NH2:23])=O)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](=[S:33])[NH2:23])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(N)=O)cc3c2)cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C(N)=S)cc3c2)cn1
Yield: 78.4 %

Procedure:
To a solution of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (4.5 g) in tetrahydrofuran (100 mL) was added a Lawesson's reagent (6 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (3.7 g, yield 78%) as yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:18]1(=[O:25])(=[O:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:21]3[CH2:22][CH2:23][S:18](=[O:25])(=[O:24])[CH2:19][CH2:20]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: O=S1(=O)CCNCC1
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCS(=O)(=O)CC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and tetrahydro-2H-1,4-thiazine 1,1-dioxide. Brown solid. MS (m/e): 353.0 ([M+H]+, 100%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[NH:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[C:22]([OH:33])[CH:23]=[C:24]([S:29](O)(=[O:31])=[O:30])[CH:25]=5)[C:19]=4[N:20]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].CN(C)C=O>S(Cl)(Cl)=O>[CH3:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[NH:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[C:22]([OH:33])[CH:23]=[C:24]([S:29]([Cl:1])(=[O:31])=[O:30])[CH:25]=5)[C:19]=4[N:20]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)O)cc(O)c54)[nH]3)c2)cc1C
Reactant: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Cl)cc(O)c54)[nH]3)c2)cc1C
Temperature: 60 °C

Procedure:
2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonic acid hydrochloride(0.08 g, 0.18 mmol) was suspended in 1 ml thionyl chloride containing catalytic amount of N,N-dimethylformamide. The reaction mixture was heated to 60° C. for 3 hours then was concentrated to dryness to give 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH3:11]>C1COCC1>[NH2:11][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][CH3:10])[N:5]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: N
Solvent: C1CCOC1
Product: CSc1nc(N)cc(Cl)n1

Procedure:
Compound 6 was prepared from commercially available 4,6-dichloro-2-(methylthio)pyrimidine followed scheme 4. To prepare compound 6.1,4,6-Dichloro-2-(methylthio)pyrimidine was reacted with ammonia in THF in a sealed tube to provide 4-Amino-6-chloro-2-(methylthio)pyrimidine in good yield. Amino group of the resulting compound was protected with suitable protecting group such as BOC to afford compound 6.1. Compound 6.1 was then reacted with methyl 4-hydroxybenzoate in the presence of base to provide the amine protected intermediate, 2 which upon deprotection under acidic condition to afford methyl 4-(6-amino-2-(methylthio)pyrimidin-4-yloxy)benzoate (3). Reaction of compound 3 with hydrazine hydrate in methanol provided 4-(6-amino-2-(methylthio)pyrimidin-4-yloxy)benzohydrazide (6.4) in good yield. The hydrazide was then reacted with S-methyl N-[3-(trifluoromethyl-phenyl)thiourea in the presence of base to yield compound 6.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:20].[ClH:21].CO>>[ClH:21].[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[NH:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]=2[CH:7]=1
Reactant: Cn1c(=O)[nH]c2ccc(CNC(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: CO
Product: Cn1c(=O)[nH]c2ccc(CN)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of tert-butyl [(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl]carbamate (658 mg, 2.37 mmol) and 10% hydrogen chloride-MeOH was stirred for 2 hours at ambient temperature. The formed precipitate was collected and washed with DCM to give the title compound as a white solid (436 mg, 86%). 1H NMR (CDCl3): δ 3.28 (3H, s), 3.73 (2H, brs), 7.01 (1H, d, J=7.9 Hz), 7.12 (1H, d, J=7.9 Hz), 7.28 (1H, d, J=8.5 Hz), 8.03-8.67 (3H, m), 11.02 (1H, s). MS (ESI) m/z 176 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:31][NH2:32].C(O)C>CO.CC(O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@@H:7]([CH2:10][C:11]([NH:32][CH3:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CN
Reactant: CCOC(=O)C[C@H]1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Solvent: CC(C)O
Solvent: CO
Solvent: CCO
Product: CNC(=O)C[C@H]1COc2cc(F)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl {(3S)-7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 14a, 1648 g) was taken up in methanol (10 L). Methylamine in ethanol (33 wt %, 20 eq., 7490 mL) was added at <30° C. The resulting solution was stirred at rt for 18 h. LCMS analysis indicated the reaction was not complete. The reaction was stirred for a further 4 h at rt after which HPLC indicated that <1% Intermediate 14a and its corresponding methyl ester remained (combined). The solvent was removed in vacuo to give the crude product as a tan solid (1719.2 g). This was combined with 376 g crude product from another batch and the combined crude product (2095 g) was taken up in IPA (20950 mL) and heated to reflux. A solution was not obtained. The suspension was sampled and the sample cooled and filtered for XRPD analysis. This indicated the product was of the desired form (type 2). HPLC analysis of the filtered material indicated a purity of 99.2% confirming purification had been successful. The suspension was cooled to room temperature over night. The solid was filtered, washed with IPA (3×2 L) and pulled dry. Further drying in a vacuum oven at 60° C. yielded the title product as an off-white solid (1632.5 g). 1H NMR indicated a purity of >95% (0.18% residual IPA). This material was combined with the product from another smaller scale recrystallisation (input 250 g crude) to give a total of 1820.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21](=O)[C:22](=[CH:23][N:24](C)C)[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:28]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]3[S:16][C:17]4[C:22]5[C:21]([CH2:20][CH2:19][C:18]=4[C:11]=23)=[N:28][NH:24][CH:23]=5)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C=C1C(=O)CCc2c1sc1ncnc(Nc3ccc(F)c(Cl)c3)c21
Reactant: NN
Solvent: CCO
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCc2n[nH]cc2-4)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.9 %

Procedure:
To a solution of 4-(3-Chloro-4-fluoro-phenylamino)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one (100 mg, 0.25 mmol) in anhydrous ethanol (2 mL) was added hydrazine (12 mg, 0.37 mmol). The resulting mixture was stirred at rt for 5 h. The solid was filtered and washed with EtOAc and then with water. It yielded N-(3-chloro-4-fluorophenyl)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine as a red solid (52 mg, 56%). 1H-NMR (DMSO-d6) δ 12.73 (s, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.61 (m, 1H), 7.40 (t, 1H), 3.40 (t, 2H), 2.96 (t, 2H); LCMS RT=2.98 min; [M+H]+=372.3.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].Cl.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:23]([NH:25][NH2:26])=[O:24])[CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOCC>[CH2:18]([C:20]1[CH:21]=[C:22]([C:23]([NH:25][NH:26][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:5]=23)=[O:10])=[O:24])[CH:27]=[C:28]([CH3:30])[N:29]=1)[CH3:19]
Reactant: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Reactant: CCc1cc(C(=O)NN)cc(C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NNC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (114 mg, 0.48 mmol), 2-ethyl-6-methyl-isonicotinic acid hydrazide hydrochloride (120.5 mg, 0.48 mmol) and DIPEA (0.49 mL) in DMF (8 mL) is added TBTU (190 mg, 0.59 mmol). The mixture is stirred at rt for 15 h. The mixture is diluted with Et2O (50 mL) and extracted with 1M aq. NaOH (2×20 mL). The aq. extracts are washed with EA (2×20 mL) and the combined organic phases are dried (MgSO4), filtered and evaporated to give crude 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazide; LC-MS: tR=0.83 min, [M+1]=400.31.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([NH2:16])[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>CC(N(C)C)=O.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].O1CCOCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([NH:16][C:18]4[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]5[CH2:26][CH2:27][CH2:28][CH2:29]5)=[CH:30][CH:31]=4)[N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: Nc1nc2cccc(NC3CCCC3)n2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: c1cc(NC2CCCC2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1
Temperature: 150 °C

Procedure:
In a microwave vial, N*5*-cyclopentyl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine (0.07 g, 0.322 mmol), 1-(2-(4-bromophenoxyl)ethyl)pyrrolidine (0.13 g, 0.483 mmol), bis(dibenzylideneacetone)palladium (0.01 g, 0.016 mmol), xantphos (0.019 g, 0.032 mmol) and sodium tert-butoxide (0.063 g, 0.644 mmol) were added successively. 1,4-Dioxane (1.2 mL) and dimethylacetamide (4 drops) were added and the vial was sealed and heated under microwave irradiation (150° C., 10 min). The mixture was filtered and purified by preparatory HPLC. LCMS Method: 2: RT: 2.51 min, MI: 407 [M+1]. NMR 1H (DMSO): 1.55-1.75 (m, 10H), 2.03-2.08 (m, 2H), 2.55-2.65 (m, 4H), 2.84 (t, 2H), 3.93-4.00 (m, 1H), 4.01 (t, 2H), 6.10 (d, 1H), 6.15 (d, 1H), 6.69 (d, 1H), 6.87 (d, 2H), 7.37 (t, 1H), 7.63 (d, 2H), 9.17 (s, 1H).