Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].[Cl:11][CH2:12][C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19])=[O:14]>C(OCC)C>[Cl-:11].[CH3:9][N+:8]([CH3:10])([CH2:12][C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19])=[O:14])[CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(C)=CCC/C(C)=C/COC(=O)CCl
Reactant: CC(=O)NCCCN(C)C
Solvent: CCOCC
Product: CC(=O)NCCC[N+](C)(C)CC(=O)OC/C=C(\C)CCC=C(C)C
Product: [Cl-]
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
A 7.21 g (0.05 mol) portion of N-acetyl-N′,N′-dimethyl-1,3-diaminopropane and 150 ml of diethyl ether were put into a flask, and 11.65 g (0.0505 mol) of geranyl chloroacetate was added thereto at 0 to 5° C. spending 10 minutes. The reaction mixture was stirred for 2 hours while cooling on ice to observe precipitation of the product. This was further stirred at 25° C. for 12 hours, and disappearance of the most part of chloroacetate was confirmed by 1H-NMR. Next, the solvent was evaporated under a reduced pressure, and the reaction mixture as the residual viscous oil was dissolved in 20 ml of dichloromethane and slowly added dropwise to 400 ml of diethyl ether which was ice-cooled and vigorously stirred, spending 5 minutes, to effect precipitation of the product as a white solid.. Thereafter, in the same manner as described in Inventive Example 1, the title compound (to be referred to as betaine ester (5) hereinafter) was obtained as a light yellow viscous oil. Yield 15.6 g (41.6 mmol; yield 83.2%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[CH2:12]([S:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCCCCCCSc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCSc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 30 %

Procedure:
4-Cyanophenylboronic acid (7 g, 0.0476 m) was stirred and refluxed for 60 hours under nitrogen with 4-n-heptylthiobromobenzene (12.4 g, 0.0433 m), TTPP (0.9 g, 0.000783 m), 2 molar aqueous sodium carbonate (41 mls). toluene (86 mls) and industrial methylated spirit (20.5 mls). The mixture was then separated and extincted with toluene (2×100 mls) washed with water (100 mls) and dried over magnesium sulphate. The solvents were then evaporated off to give a brown solid products which was purified by column chromatography and recrystallisation from industrial methylated spirit. 4-Cyano-4'-heptylthiobiphenyl was produced (4.1 g, 100% HPCL, 30% yield melting point 64.4° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 28 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a stirred solution of 2-bromo-5-fluorotoluene (1.495 g, 7.909 mmol, Aldrich, used as received) in conc. H2SO4 (10.0 mL) at 0° C., KNO3 (0.800 g, 7.91 mmol) was added in one lot. The resulting pale yellow solution was warmed to 28° C. and stirred overnight at 28° C. It was then poured into ice (50 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil dried further under vacuum to afford 1.832 g (98%) of the title compound as an oil; 1H NMR (CDCl3): δ2.495 (s, 3H), 7.213 (d, 1H, J1 =11.4 Hz), 8.268 (d, 1H, J1 =7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([S:39]([CH3:42])(=[O:41])=[O:40])[CH:34]=2)C=CC=CC=1.C(OCC)(=O)C.O>CS(C)=O>[CH3:42][S:39]([C:35]1[CH:34]=[C:33]([NH:32][C:31]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=4)[N:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)=[O:30])[CH:38]=[CH:37][CH:36]=1)(=[O:40])=[O:41]
Reactant: CSc1ccc(Nc2cc(Oc3ccc(N)cc3)ncn2)cc1
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(Nc2cc(Oc3ccc(NC(=O)Nc4cccc(S(C)(=O)=O)c4)cc3)ncn2)cc1
Yield: 94.8 %

Procedure:
N-(6-(4-Aminophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine (194 mg, 0.600 mmol) and (3-methylsulfonylphenyl)carbamic acid phenyl ester (192 mg, 0.660 mmol) were heated and stirred in dimethylsulfoxide (2 ml) at 85° C. for 18 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (297 mg, 0.569 mmol, 95%) as colorless crystals.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+].[NH4+].[Cl-]>CO>[N:14]([CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])[CH3:12])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCC(O)CN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A solution of 2-[2-[[(tert-butyl)dimethylsilyl]oxy]ethyl]-oxirane (5.0 g; prepared according to WO 2007/144423) in MeOH (150 mL) was reacted with NaN3 (3.95 g) and NH4Cl (2.37 g). The reaction mixture was further stirred at 80° C. overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between EA and water. The org layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure, affording a yellow oil (4.9 g, 81% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([CH:25]=O)=[C:20]([F:27])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1)=[O:4].[NH2:30][CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1C=CC=CC=1>[CH3:29][C:2]([CH3:1])([CH3:28])[C:3]([O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([CH2:25][NH:30][CH:31]4[CH2:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH2:32]4)=[C:20]([F:27])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[N:8]1)=[O:4]
Reactant: CC(C)(C)C(=O)OCn1cnc(-c2cccc(-c3cc(F)c(C=O)c(F)c3)c2)n1
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)OCn1cnc(-c2cccc(-c3cc(F)c(CNC4Cc5ccccc5C4)c(F)c3)c2)n1
Reaction time: 1.5 h

Procedure:
A mixture of [3-(3′,5′-difluoro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate (67.6 g; 0.17 mol; I-X-9), 2-aminoindane (22.9 g; 0.17 mol; freebase obtained commercially) and HOAc (0.48 mL; 0.0085 mol, Note 1) in PhH (350 mL) was heated under reflux using a Dean-Stark trap to remove water. After 1.5 h, volatiles were removed in vacuo, the residue was dissolved in CH2Cl2/HOAc (400:25 mL respectively), and NaBH(OAc)3 (43 g; 0.203 mol) was added at room temperature. The mixture was stirred 12 h, and quenched by dropwise addition of water (250 mL). The mixture was stirred 30 min and separated into layers. The organic layer was washed (satd NaHCO3, brine), filtered through a pad of Na2SO4 and concentrated in vacuo. The residue was triturated with MeOH (250 mL), the resulting slurry was diluted with water (250 mL) and stirred 30 min at room temperature. Solids were collected by filtration, and washed with water. The cake was air-dried overnight on the filter, affording the title compound as an off-white solid, used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (s, 9H), 2.74 (dd, J=15.7, 6.1 Hz, 2H), 3.09 (dd, J=15.8, 7.1 Hz, 2H), 3.54 (quint, J=6.6 Hz, 1H), 3.86 (s, 2H), 6.21 (s, 2H), 7.07-7.13 (m, 2H), 7.15-7.21 (m, 2H), 7.43-7.52 (m, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.81 (ddd, J=7.9, 1.8, 1.1 Hz, 1H), 8.06 (ddd, J=7.8, 1.3, 1.2 Hz, 1H), 8.26 (t, J=1.7 Hz, 1H), 8.82 (s, 1H).
Reaction SMILES: I[C@H:2]1[C@H:19]([CH3:20])[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3]1=[O:23].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[CH3:20][C:19]1[C@@:18]2([CH3:21])[C:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])=[CH:4][C:3](=[O:23])[CH:2]=1
Reactant: C[C@H]1[C@H](I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]12C
Reaction time: 1.5 h

Procedure:
2.13 g (5 mmol) of 2β-iodo-1α-methylandrost-4-ene-3,17-dione of example 1 is introduced in a suspension of 0.73 g (10 mmol) of lithium carbonate in 10 ml of dimethylformamide preheated to 130° C. and stirred for 1.5 hours at this temperature. After cooling, the reaction solution is added to 30 ml of water, extracted with ethyl acetate and after drying on sodium sulfate, concentrated by evaporation. The crude product is chromatographed on silica gel with ethyl acetate/hexane as mobile solvent. After recrystallization from ethyl acetate, 1.1 g of 1-methylandrosta-1,4-diene-3,17-dione (74% of theory) of melting point 169° C. is obtained.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].Cl[C:9]1[N:14]=[N:13][C:12]([O:15][CH2:16][CH2:17][C@@H:18]([N:20]([C:35]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]2)=[O:36])[C:21]2[CH:25]=[C:24]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])[S:23][C:22]=2[C:32]([OH:34])=[O:33])[CH3:19])=[CH:11][CH:10]=1.CC([O-])=[O:46].[Na+]>CC(O)=O.CO>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]#[C:26][C:24]1[S:23][C:22]([C:32]([OH:34])=[O:33])=[C:21]([N:20]([C@@H:18]([CH3:19])[CH2:17][CH2:16][O:15][C:12]2[N:13]=[N:14][C:9]([OH:46])=[CH:10][CH:11]=2)[C:35]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]2)=[O:36])[CH:25]=1
Reactant: CC(=O)[O-]
Reactant: C[C@@H](CCOc1ccc(Cl)nn1)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](CCOc1ccc(O)nn1)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Reaction time: 3 h

Procedure:
A mixture of 3-[[3-(6-chloro-pyridazin-3-yloxy)-1(S)-methyl-propyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid TFA salt (0.56 g, 0.087 mmol) in AcOH (2.0 mL) and NaOAc (0.37 g, 0.434 mmol) was placed in a preheated 100° C. oil bath and stirred for 3 h. The reaction was determined to be complete by LC/MS. After cooling, the reaction was diluted with CH3OH (5 mL). 5-(3,3-Dimethyl-but-1-ynyl)-3-[[3-(6-hydroxy-pyridazin-3-yloxy)-1-(S)-methyl-propyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid TFA salt (0.07 g, 13%) was isolated by reverse phase HPLC as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>CC#N>[Cl:18][CH2:19][CH2:20][C:21]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:22]
Reactant: O=C(Cl)CCCl
Reactant: NC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)c1ccccc1NC(=O)CCCl
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2-aminobenzamide (500 mg, 3.68 mmol) and triethylamine (NEt3) (450 mg, 4.41 mmol) in CH3CN (30 mL) was added 3-chloropropanoyl chloride (0.45 mL, 4.41 mmol) dropwise at room temperature. After stirring overnight, the reaction mixture was concentrated to give the desired product (800 mg) as solid, which was used for the next step without further purification. LC-MS: m/z 227 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:32])[CH:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)OS(C)(=O)=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:39]([O:43][C:44](=[O:49])[NH:45][CH2:46][CH2:47][NH2:48])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:32])[CH:19]([NH:48][CH2:47][CH2:46][NH:45][C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:49])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)n1ncc2cc(NC(=O)C(OS(C)(=O)=O)c3cccc(Cl)c3)ccc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCNC(C(=O)Nc1ccc2c(cnn2C(=O)OC(C)(C)C)c1)c1cccc(Cl)c1
Temperature: 60 °C
Yield: 85 %

Procedure:
To a solution of 5-[2-(3-chloro-phenyl)-2-methanesulfonyloxy-acetylamino]-indazole-1-carboxylic acid tert-butyl ester (1.49 mmol) in dry THF (4 mL) was added pyridine (4.48 mmol, 3 equivalents) followed by followed by a dry THF solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (3 equivalents, ˜0.5 mL/mmol). The resulting solution was refluxed at 60° C. overnight. The reaction mixture was then concentrated in vacuo and the resulting oil was partitioned between EtOAc and brine. The organic layer was washed with brine (thrice), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using eluting with EtOAc:hexane (60:40) to afford the title compound in 85% yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C>[ClH:16].[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]2[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1)(=[O:3])[CH3:2]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc(C(C)=O)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of 5-acetyloxindole (352 mg, 2 mmol), (EP 0155828 A2), in DMF (5 ml) was added to a suspension of sodium hydride (80 mg, 2 mmol, prewashed with hexane) in DMF (1 ml) and the mixture stirred for 30 minutes at ambient temperature. 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (180 mg, 0.67 mmol), (prepared as described for the starting material in Example 2), was added and the mixture was heated at 50° C. for 1.5 hours. The mixture was partitioned between water and ether and the aqueous layer was adjusted to pH7 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water and dried under vacuum. The solid was dissolved in methylene chloride/methanol (30 ml/30 ml) and 7M ethanolic hydrogen chloride (1 ml) was added. The mixture was left to stand for 15 minutes at ambient temperature, the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(5-acetyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (195 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][C:12]1[N:16]2[N:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1.[H-].[Na+].I[CH3:30].O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:30])=[CH:4][C:3]=1[CH2:11][C:12]1[N:16]2[N:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1
Reactant: Cn1cc(-c2ccc3ncc(Cc4cc5cn[nH]c5cc4F)n3n2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3ncc(Cc4cc5cnn(C)c5cc4F)n3n2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(6-Fluoro-1H-indazol-5-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 167, 18.6 mg, 0.054 mmol) was dissolved in DMF (0.310 mL) and cooled down to 0° C. NaH (1.9 mg, 0.080 mmol) was added and the RM was stirred for 30 min. Then iodomethane (4.02 μL) was introduced and it was allowed to warm up to rt. After 2.5 h of stirring, water was added and it was extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 1.0 min (conditions 2), MH+=362).
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].CCN(C(C)C)C(C)C.O=S(Cl)[Cl:45]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:33])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[CH:17]=[N:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)[Cl:45])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(Oc2ccc(C(O)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2ccc(C(Cl)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of alcohol (535 mg, 1.14 mmol) from step 2 and i-Pr2NEt (436 mL, 2.5 mmol) in 10 mL of anhydrous toluene, was slowly added SOCl2 (145 mnL, 2.0 mmol). The resulting yellow solution was stirred 30 minutes at 0° C., 10 minutes at room temperature, quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was used directly for the next step without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].P(O)(O)O.[H][H]>[Ti].[Pt].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[NH2:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [H][H]
Agent: [Pt]
Agent: [Ti]
Agent: OP(O)O
Solvent: O
Product: Nc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 0.38 h
Yield: 90 %

Procedure:
A titanium autoclave equipped with a jacket for heating, coils for circulating temperature controlled water and an efficient agitator was charged with 300 parts of 3,4-dichloronitrobenzene, 0.30 part of phosphorous acid and 0.006 part of platinum (the actual charge consisting of an aqueous paste of platinum deposited on a carbon support, the quantity of platinum on the support being 5.0 weight % on a dry basis). Air in the autoclave and lines was displaced by pressuring with nitrogen and releasing the pressure through a vent system. The nitrogen was then displaced by pressurizing with hydrogen to 300 p.s.i.g. and releasing the pressure as before. The temperature of the mixture was then raised to 90° C., the agitator was started and the hydrogen pressure was increased to about 500 p.s.i.g. Absorption of hydrogen was rapid with evolution of heat; the temperature of the reaction mass was held at 115° ± 5° C. by circulating low pressure steam through the coils. The autoclave was repressured with hydrogen to 500 p.s.i.g. after each 100 lb. drop in pressure. When no further hydrogen absorption occurred, the mass was held at the operating temperature and 500 p.s.i.g. hydrogen pressure for 15-30 minutes. The total hydrogenation time was 1.25-1.50 hours. The hot reduction mass was cooled to below 100° C., removed from the autoclave, treated with ammonium hydroxide (to a pH above 7.0) and then filtered. The filtrate was allowed to settle at 70°-85° C. and the layers were separated. Analysis of the organic layer by gas chromatography showed the presence of 0.04 mole % of dechlorination products. If desired, the dichloroaniline product can be distilled in the presence of 2 weight % soda ash and 0.25 weight % tetraethylenepentamine, for example, as described in U.S. Pat. No. 2,911,340, to give 3,4-dichloroaniline of greater than 98% purity in greater than 90% yield.
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:26]=[CH:27][C:28](C4C=C5C(C=NN5C)=CC=4)=[N:29][CH:30]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11].[C:51](#[N:53])[CH3:52]>O>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([C:18]4[CH:15]=[C:52]5[C:21](=[CH:20][CH:19]=4)[N:22]([CH3:23])[N:53]=[CH:51]5)[CH:26]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:16]([OH:17])=[O:6])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC#N
Reactant: Cc1cc2nc(-c3ccc(-c4ccc5cnn(C)c5c4)nc3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Product: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O) to a volume of 114 mL. This stock solution (0.3 mL) was added to a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-6-yl)pyridin-5-yl)benzo[d]thiazol-6-yl)ethanol (15 mg, 0.027 mmol) in 0.75% H2O in ACN (3 mL). The reaction mixture was stirred at room temperature for 45 minutes, quenched with saturated Na2SO3 solution and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (H2O/ACN+0.1% TFA) to give the desired product after lyophilization. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.2 (M+H+); found: 597.2, 599.2. 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 8.98 (s, 1H), 8.67 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.83 (dd, J=8.8, 1.6 Hz, 1H), 7.73 (dd, J=13.4, 5.2 Hz, 2H), 7.60 (d, J=8.0 Hz, 3H), 5.27 (s, 1H), 4.11 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H) (115).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1CC(O)=O.CN(C=O)C>C(Cl)Cl>[CH:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:14]=1[CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
Oxalyl chloride (7.0 mL, 80.2 mmol) was added under nitrogen to a solution of 2-naphthylacetic acid (3.00 g, 16.1 mmol) in 150 mL of methylene chloride at room temperature. A catalytic amount of DMF (10 μL) was added and the reaction stirred at room temperature for 3 h. The solvent and excess oxalyl chloride were removed under reduced pressure. To remove any residual oxalyl chloride the residue was taken up in benzene and then concentrated under reduced pressure to give naphthalen-2-yl-acetyl chloride (3.20 g, 99%) as a yellow solid that was used in the next step without additional purification