Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S)=CC=1.C(N(CC)CC)C.[Cl:16][C:17]1[S:18][C:19]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][C:21]=1[Cl:22].O>ClCCl>[Cl:16][C:17]1[S:18][C:19]([S:23]([OH:25])=[O:24])=[CH:20][C:21]=1[Cl:22]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Agent: Cc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=S(O)c1cc(Cl)c(Cl)s1
Temperature: 78 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A solution of p-thiocresol (4.94 g, 39.8 mmol), triethylamine (5.55 mL, 39.8 mmol) in dichloromethane (30 mL) was added dropwise over 12 minutes to a solution of 2,3-dichlorothiophene-5-sulfonyl chloride (5.0 g, 19.9 mmol) in dichloromethane (50 mL) at -78° C. under a dry nitrogen atmosphere. An additional 10 mL of dichloromethane was added and the reaction mixture was stirred at-78° C. for 2 h and then warmed to room temperature over 20 minutes. The reaction mixture was poured into water (400 mL) and the layers were separated. The dichloromethane phase was washed with water (2×200 mL) and the combined aqueous phase was acidified with concentrated HCl. Solid NaCl was also added to the aqueous phase which was then extracted with ether (4×200 mL). The extracts were combined and dried (Na25SO4) and concentrated to afford 2,3-dichlorothiophene-5-sulfinic acid as a white solid (2.89 g, 67%): NMR (DMSO, d 6): δ 9.1 (broad s, 1H, O H), 7.54 (s, 1H, thiophene H); MS(EI): 216, 218, 220 (70, 50, 10%, MI), 199, 201, 203 (60, 50, 10%,--OH), 169 (50%), 167 (70%), 154 (70%), 152 (100%).This ulfinic acid (2.33 g, 10.73 mmol) was dissolved in a solution of sodium hydroxide (0.42 g, 10.73 mmol) in methanol (25 mL) at room temperature. The methanol was removed and residual water was removed by azeotroping with benzene to provide 2,3-dichlorothiophene-5-sulfinic acid, sodium salt of formula (IV) as a whir solid (2.57 g, 100%): NMR (DMSO, d6): δ 6.89 (s, 1H, thiophene H); Anal. Calc. for C4HCl2O2S2 : C, 20.09; H, 0.41; Found: C, 19.80; H, 0.52. This sulfinic acid, sodium salt of formula (IV) (2.12 g, 8.87 mmol) was mixed with 5-bromo-thiazolidine-2,4-dione (1.58 g, 8.06 mmol) and Aliquat 336 (tricaprylylmethylammonium chloride, 0.45 mL) and allowed to stand overnight. Dilute aqueous HCl (100 mL) was added and the aqueous reaction mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine and concentrated. The crude product was purified by flash chromatography using acid washed (2% H3PO4 in methanol) silica gel and 82:18 ethyl acetate: petroleum ether as eluant to provide the title compound of formula (V) as a white solid: mp 176°-177° C: NMR (DMSO, d 6): δ 13.0 (broad s, 1H,N H), 8.10 (s, 1H, thiophene H); 6.85 (s, 1H, C H); MS(E1): 331,333, 335 (30, 20, 5%, MI), 215, 217, 219 (100, 70, 15%); Anal. Calc. for C7H3Cl2NO4S3 : C, 25.31; H, 0.91; N, 4.22; Found: C, 25.83; H, 1.00; N, 4.23.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:36][N:37]([CH3:48])[CH2:38][CH2:39][NH:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([CH3:47])[CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][N:37]([CH3:48])[CH2:38][CH2:39][N:40]([C@H:41]1[CH2:42][CH2:43][C@H:44]([CH3:47])[CH2:45][CH2:46]1)[C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:12][C:2]=1[Cl:1]
Reactant: O=C(O)C=Cc1ccc(OC2CCCCO2)cc1Cl
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1ccc(OC2CCCCO2)cc1Cl)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.7 g of 2-chloro-4-(2-tetrahydropyranyloxy)cinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that performed in Example 81 was carried out. As a result, 3.01 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-2-chloro-4-(2-tetrahydropyranyloxy)cinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](O)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:12][CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of 5.0 g (0.028 mol) 1,2,3,4-tetrahydro-2-naphthoic acid in 30 ml of dry tetrahydrofuran, 1.1 g (0.029 mol) lithium aluminum hydride was added over a period of one half hour. After the addition was completed, the mixture was stirred at room temperature for a period of 2 hours. It was then cooled on ice, and was carefully decomposed with a minimum amount of saturated Na2SO4 solution. The reaction mixture was filtered and washed with ether. The organic layer was combined and extracted with water. Concentration of the dried organic layer yielded 4.4 g of crude product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20]CC2C=CC(OC)=CC=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([SiH](CC)CC)C.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([OH:20])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCc1cc(OCc2ccccc2)c(O)cn1

Procedure:
A solution of {5-({[4-(methyloxy)phenyl]methyl}oxy)-4-[(phenyl methyl)oxy]-2-pyridinyl}methyl acetate (containing triphenylphosphine oxide as an impurity) (20 g, 50.8 mmol) in dichloromethane (500 ml) was treated with triethylsilane (10 ml, 62.6 mmol). A solution of trifluoroacetic acid (35 ml, 0.45 mol) in dichloromethane (200 ml) was added over 1 hour. After 2 hours the mixture was evaporated and chromatographed on silica gel eluting with 50-100% ethyl acetate-hexane, then 5-10% methanol-DCM affording a solid, the TFA salt in a 1:1 mixture with triphenylphosphine oxide (8.33 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH2:21][CH2:22][CH3:23].[CH3:24][CH2:25][O:26][C:27]([CH:29](P(OCC)(OCC)=O)[F:30])=[O:28].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:29](/[F:30])\[C:27]([O:26][CH2:25][CH3:24])=[O:28])[C:3]=1[O:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1c(/C(C)=C(/F)C(=O)OCC)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-8-isopropyl-5,5-dimethyl-3-propoxy-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-113, 202 mg, 0.53 mmol) and triethyl 2-fluoro-2-phosphonoacetate (516 mg, 2.12 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.33 mL, 2.12 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+].[O:14]([C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2=[N:25][CH2:26][CH2:27][N:17]12)O.CN(C)C=O>O>[C:16]([C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:18]1[NH:25][CH2:26][CH2:27][N:17]=1)(=[O:14])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OOC1(c2ccccc2)c2ccccc2C2=NCCN21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccccc1C1=NCCN1

Procedure:
A solution of 0.7 g. of sodium sulfite heptahydrate in 3 ml. of water was added to 0.5 g. of 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole in 7 ml. of dimethylformamide. The solution was heated to 100° for 15 minutes. On cooling and addition of 20 ml. of water, 2-(2-benzoylphenyl)-2-imidazoline was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=N[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=CC=[C:27]([F:31])C=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:27]([F:31])[CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Fc1cccc(Br)c1
Product: Cc1ccc(Nc2cccc(F)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a light brown solid, MS (ISP): m/e=326.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16]>>[C:3]1([CH2:2][S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]([OH:22])=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C(O)c1ccccc1S
Reactant: ClCc1nccc2ccccc12
Product: O=C(O)c1ccccc1SCc1nccc2ccccc12

Procedure:
Following the procedure described in Example 16 but starting from 1.8 g. of 1-chloromethyl-isoquinoline and 1.54 g. of thiosalicylic acid, 1.1 g. of S-(1-isoquinolyl-methyl)-2-mercapto-benzoic acid are obtained, melting at 170° to 172° C.
Reaction SMILES: CN1C(=O)CCC1.N1(O[C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[C:21]([C:32]([NH2:34])=[O:33])=[CH:20][N:19]=2)C2C=CC=CC=2N=N1.[Br:35][C:36]1[CH:37]=[C:38]([CH2:43][CH2:44][NH2:45])[CH:39]=[CH:40][C:41]=1[OH:42].C(N(C(C)C)CC)(C)C>O>[Br:35][C:36]1[CH:37]=[C:38]([CH2:43][CH2:44][NH:45][C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[C:21]([C:32]([NH2:34])=[O:33])=[CH:20][N:19]=2)[CH:39]=[CH:40][C:41]=1[OH:42]
Reactant: NCCc1ccc(O)c(Br)c1
Reactant: Cc1cccc(Nc2nc(On3nnc4ccccc43)ncc2C(N)=O)c1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Nc2nc(NCCc3ccc(O)c(Br)c3)ncc2C(N)=O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
A 6 ml portion of NMP solution containing 600 mg of 2-(benzotriazol-1-yloxy)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide was mixed with 538 mg of 2-(3-bromo-4-hydroxyphenyl)ethylamine and 0.72 ml of diisopropylethylamine, followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, the solvent was evaporated, and then the resulting residue was recrystallized (ethanol-THF) to obtain 200 mg of 2-{[2-(3-bromo-4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:39][CH2:38][C:37]5[N:36]=[C:35]([CH2:40][CH2:41][CH3:42])[C:34]([C:43]([O:45]CC)=[O:44])=[CH:33][C:32]=5[C:31]4=[O:48])[CH2:26][CH2:25]3)[CH:7]=2)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH2:39][CH2:38][C:37]5[N:36]=[C:35]([CH2:40][CH2:41][CH3:42])[C:34]([C:43]([OH:45])=[O:44])=[CH:33][C:32]=5[C:31]4=[O:48])[CH2:28][CH2:29]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OCC)CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OCC)CC1)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
2M aqueous sodium hydroxide solution (25 mL) was added to a solution of ethyl 6-(1-((6-cyclopropyl-3-ethoxy-2,4′-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (7.98 g) in ethanol (65 mL) at room temperature. The mixture was stirred at 80° C. under nitrogen atmosphere for 2 hours and concentrated in vacuo. The residue was dissolved in water. The solution was adjusted to neutral with 2M hydrochloric acid to give colorless crystals. After filtration, the crystals was dissolved in ethanol. The solution was filtrated and the filtrate was concentrated in vacuo. The residue was crystallized from ethyl acetate-hexane to give a colorless solid. The solid was recrystallized from ethanol-hexane to give the title compound (7.16 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[Cl:32][CH2:33][C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(trifluoromethyl)benzamide (200 mg, 0.450 mmol) produced in Example C8(iv) in N,N-dimethylformamide (5 mL) was added chloroacetyl chloride (104 μL, 0.900 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with a mixed solution of ethyl acetate and hexane to give the title compound (218 mg, 93%) as a white powder. The powder was used for the next reaction without further purification operation.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][S:16]([CH2:19][C:20](O)=[O:21])(=[O:18])=[O:17])=[CH:13][CH:12]=1>C(O)(=O)C>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][S:16]([C:19]2[C:20](=[O:21])[O:4][C:3]3[C:2]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)(=[O:17])=[O:18])=[CH:13][CH:12]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccccc1O
Solvent: CC(=O)O
Product: O=c1oc2ccccc2cc1S(=O)(=O)Cc1ccc(Cl)cc1
Yield: 99 %

Procedure:
A solution of salicylaldehyde (1 mmol) and 2-(4-chlorobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 99% yield of the title compound; m.p. 195-196° C.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[C:6]([I:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:12].C(N(S(F)(F)[F:19])CC)C>ClCCl>[F:19][C:7]1[C:6]([I:11])=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][C:3](=[O:12])[CH2:4]2
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Cc2c(I)cccc2N1O
Solvent: ClCCl
Product: O=C1Cc2c(ccc(F)c2I)N1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1,3-dihydro-1-hydroxy-4-iodo-2H-indol-2-one, (2.43 g, 9 mmol) (see below) in dry dichloromethane (500 mL) was cooled to -25° C. under an argon atmosphere with magnetic stirring. A solution of (diethylamino)sulfur trifluoride (DAST, 1.35 mL) (Aldrich) in dry dichloromethane (40 mL) was added dropwise at such a rate that the reaction temperature did not rise above -25° C. (about 15 min.). After stirring for an additional 30 min. at -25° C., the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (180 mL) and allowed to warm to room temperature. The mixture was then filtered through Celite® (Fisher Scientific) and the layers separated. The aqueous layer was extracted with dichloromethane (2×300 mL). The dichloromethane layers were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (magnesium sulfate) and concentrated. Residue was purified by flash chromatography on silics gel using ethyl acetate-dichloromethane (1:7, V/V) as solvent to give 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one. (Yield 1.08 g, 43%).
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([CH2:21][O:22]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:16][C:17]([O:19][CH3:20])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:13][CH2:14][CH:15]([CH2:21][OH:22])[O:16][C:17]([O:19][CH3:20])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCOCC(CO)OC(=O)OC
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 107.4 %

Procedure:
To a solution of (rac)-1-O-dodecyl-2-O-methoxycarbonyl-3-O-trityl-glycerol (10.2 g) in methylene chloride (100 ml) was added trifluoroacetic acid (10 ml) in one portion. After the yellow solution was stirred for 8 minutes at ambient temperature, ice water (100 ml) was added. The organic layer was washed with aqueous sodium bicarbonate solution and water, dried, and evaporated under reduced pressure. The residue was treated with n-hexane (50 ml) to remove triphenylmethanol as a white crystal. The filtrate was evaporated to give 6.22 g of (rac)-1-O-dodecyl-2-O-methoxycarbonyl-glycerol as a colorless oil (unstable oil).
Reaction SMILES: NC1C=CSC=1C(OC)=O.[F:11][C:12]([F:26])([F:25])[C:13]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23][CH3:24])=[O:22])=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([Li])CCC.[Br:45]CCBr>>[Br:45][C:19]1[S:18][C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([NH:15][C:13](=[O:14])[C:12]([F:11])([F:25])[F:26])[CH:20]=1
Reactant: BrCCBr
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Agent: COC(=O)c1sccc1N
Agent: [Li]CCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F

Procedure:
In reaction scheme 5 the synthesis of compound B53 is described. The intermediate 3-amino-5-bromo-thiophene-2-carboxylic acid methyl ester (compound B54b) is obtained according to a procedure described in literature (Bioorganic & Medicinal Chemistry Letters 17 (2007) 2535-2539) by conversion of methyl 3-aminothiophene-2-carboxylate to methyl 3-[(trifluoroacetyl)amino]thiophene-2-carboxylate with trifluoroacetic acid anhydride followed by a lithiation/bromination sequence using n-butyllithium and 1,2-dibromoethane to give methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate which is hydrolysed under basic conditions using potassium carbonate to obtain 3-amino-5-bromo-thiophene-2-carboxylic acid methyl ester (compound B54b).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][CH:34]([NH:36][CH3:37])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][CH:34]([NH:36][CH3:37])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:31])[F:29])[CH:3]=1
Reactant: CNC1CNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CNC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[3-(methylamino)azetidin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and Azetidin-3-yl-methyl-amine following General Procedure C.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[O:15][CH3:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1cc(O)ccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
Sodium hydride (60 wt %, 3.2 g) was added to dimethyl sulfoxide (50 ml), and the mixture was stirred at 50° C. for 20 min. 4-Amino-3-methoxyphenol (5.6 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinazoline (7.0 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by suction filtration to give the title compound (7.3 g, yield 72%).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.[CH3:41][N:42]1[CH2:47][CH2:46][CH2:45][CH:44]([CH2:48]O)[CH2:43]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:48][CH:44]4[CH2:45][CH2:46][CH2:47][N:42]([CH3:41])[CH2:43]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: CN1CCCC(CO)C1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCCN(C)C1
Reaction time: 18 h
Yield: 32.5 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), 1-methyl-3-piperidinemethanol (115 mg, 0.89 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (1.5 ml of a 1M solution, 1.5 mmol) was added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (75/8/1). The purified solid product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline (105 mg, 33%).