Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][O:6][C:5]([CH2:14][S:15][CH2:16][C:17]([N:19]2[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][O:21][C:20]2=[O:30])=[O:18])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[CH:40][C:41]2[CH:55]=[CH:54][C:44]([O:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:43][CH:42]=2)=[CH:35][CH:34]=1.C(N(C(C)C)C(C)C)C.C(O)(C)C>C(Cl)Cl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].Cl[Ti](Cl)(Cl)Cl.O>[CH3:1][C:2]1([CH3:31])[CH2:3][O:4][C:5]([CH2:14][S:15][C@@H:16]([C:17](=[O:18])[N:19]2[C@@H:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][O:21][C:20]2=[O:30])[C@H:40]([C:41]2[CH:55]=[CH:54][C:44]([O:45][CH2:46][C:47]([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:48])=[CH:43][CH:42]=2)[NH:39][C:36]2[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH2:7]1
Reactant: CC1(C)COC(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)(c2ccccc2)OC1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=Nc2ccc(F)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(CS[C@@H](C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@@H](Nc2ccc(F)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccccc2)OC1
Temperature: -30 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
Tetraisopropyl orthotitanate (0.51 ml, 1.8 mmol) was added to a solution of TiCl4 (1M in CH2Cl2, 5.1 ml, 5.1 mmol) in CH2Cl2 (50 ml) at 0° C. under inert atmosphere. The mixture was stirred for ten minutes. (4S)-3-({[(5,5-Dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}acetyl)-4-phenyl-1,3-oxazolidin-2-one (3.0 g, 6.8 mmol) in dry CH2Cl2 (50 ml) was added dropwise over 20 minutes. After ten minutes, tert-butyl (4-{[(4-fluorophenyl)imino]methyl}phenoxy)acetate (4.5 g, 13.6 mmol) in dry CH2Cl2 (50 ml) was added dropwise over 30 minutes. The mixture cooled to −30° C. and stirred for 20 minutes. Ethyl diisopropyl amine (2.3 ml, 13.4 mmol) in 20 ml dry CH2Cl2 was added dropwise over ten minutes and the mixture was stirred at −30° C. for six hours. The mixture was cooled to −78° C. Isopropanol (60 ml) was added and the temperature was risen overnight. H2O (100 ml) was added and the mixture was stirred for 35 minutes at room temperature. The mixture was extracted twice with diethyl ether. The combined organic layers were washed with water, dried (MgSO4) and concentrated under reduced pressure. Purification by flash-chromatography (hexane:EtOAc 5:1) afforded 2.95 g (56%) of the title compound as a yellow solid. M/z: 793.3 (M++Na).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH2:17][CH2:18][N:19]4[CH:23]([CH:24]=3)[CH2:22][CH2:21][CH2:20]4)=[C:10](Br)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1>[C:1]([N:4]1[C:12]2[CH:11]=[C:10]3[C:16]4([CH2:15][O:14][C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH2:24][CH:23]1[N:19]([CH2:20][CH2:21][CH2:22]1)[CH2:18][CH2:17]4)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(OCC3=CC4CCCN4CC3)c(Br)cc21
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(=O)N1CCc2cc3c(cc21)C1(CCN2CCCC2C1)CO3
Yield: 77.9 %

Procedure:
1-Acetyl-6-bromo-5-[(1,2,3,5,6,8a-hexahydroindolizin-7-yl)methoxy]indoline (D3) (0.118 g, 0.3 mmol) and α,α'-azoisobutyronitrile (0.04 g) were stirred at reflux under Ar in benzene (40 ml) as tributyltin hydride (0.24 ml, 0.9 mmol) was added dropwise in benzene (10 ml) over 10 min. The mixture was stirred at reflux for 6 h, cooled, and extracted with dil. HCl. The extract was basified with saturated K2CO3, and extracted with chloroform. The organic extract was dried (Na2SO4) and evaporated to give the title compound (0.073 g, 77%) as a brown gum. NMR showed a mixture of two isomers.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:28])[CH2:23][C:24]([NH:26][NH2:27])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:27][NH:26][C:24](=[O:25])[CH2:23][N:22]([CH3:28])[CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN(C)CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)CC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (40 mL) were added 2-(dimethylamino)acetohydrazide 240 (0.32 g, 1.68 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.40 g, 3.36 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-N′-[(dimethylamino)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 241 (0.15 g, 44.5%) as a white solid.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25](OC4C=CC(F)=CC=4)[CH2:24][CH2:23]3)[CH3:19])[O:14]CCO2)=[CH:6][CH:5]=1.Cl.[C:37]1(N)[C:42]([F:43])=[C:41](F)[C:40](F)=[C:39](N)[C:38]=1F.Cl.Cl>CO>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:14])[CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:39]3[CH:38]=[CH:37][C:42]([F:43])=[CH:41][CH:40]=3)[CH2:26][CH2:27]2)[CH3:19])=[CH:8][CH:9]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccc(F)cc2)CC1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: CO
Product: CN(CCCC(=O)c1ccc(F)cc1)CCN1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 11.4 g (21.4 mmol) of 1-{2-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylamino}ethyl}-4-(4-fluorophenoxy)piperidine dihydrochloride, 260 ml of methanol and 130 ml of 3N HCl was heated at reflux for 3 hours under nitrogen. The mixture was allowed to cool to room temperature and the methanol evaporated. The mixture was made basic with saturated sodium carbonate, extracted twice with ether, washed with saturated sodium chloride and dried over potassium carbonate. Evaporation of the solvent provided an oil. The yield of the dihydrochloride was 8.38 g (79.9%). Recrystallization from ethanol/methanol provided analytically pure material.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])=[CH:20][CH:19]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][O:28][C:24]=3[C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[O:30])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Product: CC(F)(F)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)n1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][CH2:45][CH:44]([CH:47]3[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]3)[CH2:43][CH2:42]2)=[C:37]([F:54])[C:36]=1[F:55])[CH2:31][CH2:32][CH3:33].O>C1COCC1.C1(C)C=CC=CC=1>[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:42][CH2:43][CH:44]([CH:47]3[CH2:52][CH2:51][C:50](=[CH:2][O:3][CH3:4])[CH2:49][CH2:48]3)[CH2:45][CH2:46]2)=[C:37]([F:54])[C:36]=1[F:55])[CH2:31][CH2:32][CH3:33]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCOc1ccc(C2CCC(C3CCC(=O)CC3)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(C2CCC(C3CCC(=COC)CC3)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (7.9 g) and THF (100 ml) were mixed under an atmosphere of nitrogen, and cooled to −30° C. Then, potassium t-butoxide (t-BuOK) (2.6 g) was added in four portions in the temperature range of −30° C. to −20° C. After the stirring at −20° C. for another 30 minutes, the compound (24) (6.8 g) dissolved in THF (35 ml) was added dropwise in the temperature range of −30 to −20° C. After the mixture had been stirred at −10° C. for 30 minutes, the reaction solution was poured into a mixture water (200 ml) and toluene (100 ml) and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed with water and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the resulting residue was purified with a fractional operation by means of column chromatography using silica gel as a stationary phase powder and toluene as an eluent. The resulting eluent was concentrated under reduced pressure to leave 4-(4-butoxy-2,3-difluorophenyl)-4′-methoxymethylene-bicyclohexyl (25) (7.2 g). The yield based on the compound (24) was 95.5%.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=3)[C:16]([O:18]CC)=[O:17])[S:10][C:6]=2[C:5]([F:24])=[CH:4][C:3]=1[F:25].[OH-].[Na+]>O.O1CCOCC1>[F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=3)[C:16]([OH:18])=[O:17])[S:10][C:6]=2[C:5]([F:24])=[CH:4][C:3]=1[F:25]
Reactant: CCOC(=O)c1cccc(CCc2nc3c(F)c(F)cc(F)c3s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CCc2nc3c(F)c(F)cc(F)c3s2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.5 %

Procedure:
To a solution of ethyl 3-[2-(4,5,7-trifluorobenzothiazol-2-yl)ethyl]benzoate (133 mg, 0.36 mmol) in a mixture of water (5 ml) and dioxane (5 ml) was added dropwise aqueous 2N sodium hydroxide (2 ml) and the mixture was stirred for 7 hours at ambient temperature. The reaction mixture was diluted with water and then washed with ether. The aqueous layer was acidified with 10% hydrochloric acid and extracted with ethyl acetate. After drying, evaporation of the solvent left crude crystals, which were recrystallized from ether to give 3-[2-(4,5,7-trifluorobenzothiazol-2-yl)ethyl]benzoic acid (82 mg, 68%) as colorless crystals.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:33])[C:8]1=[O:34])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:34])[N:9]([CH3:33])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:31][CH:30]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccnc3)cnc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(pyridin-3-yloxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (10.3 mg, 0.021 mmol) in THF (5 mL) and water (5 mL), was added LiOH.H2O (1.80 mg, 0.042 mmol) The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(pyridin-3-yloxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6 mg, 61.8% yield) as a white solid. 1H NMR (CDCl3) δ: 8.39 (d, J=4.6 Hz, 1H), 8.33 (d, J=4.5 Hz, 2H), 7.24 (d, J=4.7 Hz, 1H), 7.17 (s, 4H), 7.10 (dd, J=8.4, 1.6 Hz, 1H), 4.75 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 3.71 (s, 3H), 3.62-3.49 (m, 2H), 2.99 (t, J=6.8 Hz, 1H), 2.00-1.84 (m, 2H). LCMS: MH+ 453 and TR=1.963 min.
Reaction SMILES: C1(=O)NC(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[CH:40]=[C:39]2[C:35]([C:36]([C:61]#[N:62])=[C:37]([C:42]3[CH:43]=[N:44][CH:45]=[C:46]([CH:48]([N:50]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:49])[CH:47]=3)[N:38]2[CH3:41])=[CH:34][CH:33]=1.O.NN.Cl>C1COCC1.C(OCC)(=O)C.C(O)C>[NH2:50][CH:48]([C:46]1[CH:47]=[C:42]([C:37]2[N:38]([CH3:41])[C:39]3[C:35]([C:36]=2[C:61]#[N:62])=[CH:34][CH:33]=[C:32]([Cl:31])[CH:40]=3)[CH:43]=[N:44][CH:45]=1)[CH3:49]
Reactant: CC(c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ammonium acetate (0.567 g, 7.207 mmol) is added to a solution of 2-(5-acetyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (0.470 g, 1.441 mmol) in MeOH (10 mL), and the reaction is stirred at 50° C. for 48 h. Sodium triacetoxyborohydride (2.251 g, 10.09 mmol) is added and the reaction is stirred for 24 h at 50° C. Additional sodium triacetoxyborohydride (2.251 g, 10.09 mmol) is added and the reaction is stirred for another 24 h at 50° C. It is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 6-chloro-2-[5-(1-hydroxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile and minor amounts of 2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile. The mixture is redissolved in THF (5 mL) and phthalimide (0.181 g, 1.206 mmol) and triphenylphosphine (0.172 g, 0.804 mmol) are added, followed with di-isopropylazodicarboxylate (0.157 mL, 0.804 mmol). The reaction is stirred at room temperature for 4 h. It is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo, to give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford a mixture of 6-chloro-2-{5-[1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-pyridin-3-yl}-1-methyl-1H-indole-3-carbonitrile and triphenyl phosphine. The mixture is redissolved in ethanol (5 mL). Hydrazine hydrate (65%) (0.411 mL, 8.506 mmol) is added and the reaction is stirred at room temperature overnight. It is then acidified with 2M aqueous HCl and concentrated in vacuo. The residue is redissolved in dichloromethane and filtered through celite to remove the precipitate formed. The organic layer is washed with water. The aqueous layer is separated and basified to with 4M aqueous NaOH, and then extracted with dichloromethane thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford 2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile as a solid. MS (ESI) m/z 311.1 (M+H)+
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][N+:14]([O-:16])=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][N+:14]([O-:16])=[O:15])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1cccc(S(=O)(=O)C[N+](=O)[O-])c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(S(=O)(=O)C[N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of [3-(1-hydroxyethyl)phenylsulphonyl]nitromethane (1.10 g, 4.5 mmol) in dichloromethane (10 ml) was added to a vigorously stirred suspension of pyridinium chlorochromate (1.45 g, 6.7 mmol) in dichloromethane (10 ml). The mixture was stirred for 2 hours. Ethyl acetate (100 ml) was added and the solvent was decanted. The black residue was washed twice with ethyl acetate. The extracts and the decanted solution were combined and filtered through magnesium silicate [`Florisil` (trade mark)]. The solvent was evaporated. The residual yellow solid was recrystallised from toluene to give (3-acetylphenylsulphonyl)nitromethane, as a solid, (0.67 g), m.p. 99°-100° C., microanalysis, found: c, 44.7; H, 3.8; N, 5.7%; C9H9NO5S requires: C, 44.4; H, 3.7; N, 5.8%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C:5]([NH2:14])=[C:4]([NH2:15])[C:3]=1[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1.[S:21](=NC1C=CC=CC=1)=O.Cl[Si](C)(C)C>N1C=CC=CC=1>[F:8][C:7]1[C:2]([F:1])=[C:3]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:4]2=[N:15][S:21][N:14]=[C:5]2[C:6]=1[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1c(N)c(-c2cccs2)c(F)c(F)c1-c1cccs1
Reactant: O=S=Nc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: Fc1c(F)c(-c2cccs2)c2nsnc2c1-c1cccs1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
2,3-difluoro-1,4-di(2-thienyl)-5,6-diamino-benzene (1.2 g, 3.9 mmol) was added into a small flask and purged with Ar three times. Then, dry pyridine (24 ml), N-thionylaniline (1.08 g, 7.8 mmol) and chlorotrimethylsilane (0.76 g, 7.0 mmol) were added. The mixture was stirred at 80° C. for 16 h before poured into ice water. The yellow precipitate was then filtered and washed with a mixture of ethanol and water (1:1 v/v) to afford 5,6-difluoro-4,7-di(2-thienyl)-2,1,3-benzothiadiazole as a yellow solid (1.3 g, 98%). 1H and 19F NMR spectra were as expected.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[N:39]1([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[OH:47][CH2:46][CH2:45][N:39]1[CH2:44][CH2:43][N:42]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:41][CH2:40]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: OCCN1CCNCC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCN(CCO)CC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 1-piperazineethanol were converted to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:25](=[O:26])[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of 5-bromoindoline (13.86 g) and triethylamine (8.50 g) in dichloromethane (100 mL) was added dropwise phenylacetyl chloride (11.9 g) at 5° C. and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to give 5-bromo-1-(phenylacetyl)indoline (16.01 g) as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:18]=[C:17]([C:29]([OH:32])([CH3:31])[CH3:30])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:19]2[N:20]=[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=[C:17]([C:29]([OH:32])([CH3:31])[CH3:30])[CH:18]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cc3ccc(Cl)cc3)cc(C(C)(C)O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 119 %

Procedure:
To a solution of 4-[4-(4-chloro-benzyl)-6-(1-hydroxy-1-methyl-ethyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.447 mmol) in dichloromethane (5 mL) was added at 0° C. trifluoroacetic acid (365 μL, 4.77 mmol) and the mixture was stirred for 18 hours while allowing to warm to ambient temperature. It was basified by addition of 1 M aqueous sodium carbonate solution (5 mL) and extracted with dichloromethane (15 mL). The organic layers were washed with 1 M aqueous sodium carbonate solution (15 mL) and dried over sodium sulfate. Concentration afforded the title compound (192 mg, 99%) as a brown semi-solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:14][C:13]([C:15]([O:17]C)=[O:16])=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)[CH2:11][C:10]=2[C:27]([O:29]C)=[O:28])=[CH:4][CH:3]=1.[Na].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+].Cl>O.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[CH:11][C:10]=2[C:27]([OH:29])=[O:28])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Nc2ccc(Br)cc2)CC(C(=O)OC)=C(Nc2ccc(Br)cc2)C1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Nc2ccc(Br)cc2)c(C(=O)O)cc1Nc1ccc(Br)cc1
Yield: 95.6 %

Procedure:
Dimethyl 2,5-bis{(4-bromophenyl}amino]cyclohexa-1,4-diene-1,4-dicarboxylate (5.36 gm; 10 mmol) the sodium salt of 3-nitrobenzenesulphonic acid (2.3 gm; 10 mmol), ethanol (50 ml) and 1.0M sodium hydroxide (30 ml) were heated to reflux for 7 hours under a nitrogen atmosphere. The bright yellow solution was allowed to cool and water (120 ml) was added. The mixture was acidified with conc. hydrochloric acid when a magenta solid precipitated out. This material was filtered off, washed with water and dried under vacuum over phosphorous pentoxide to give 4.84 gm (96%) of 2,5-bis{(4-bromophenyl)amino}terephthalic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[CH:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][C:11](=[O:13])[CH3:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 100.1 %

Procedure:
To a solution of 1H-indol-6-ol (1.5 g, 11.4 mmol) and acetic anhydride (1.2 mL, 12.6 mmol) in DCM (114 mL) was added Et3N (3.18 mL, 22.8 mmol) and the reaction mixture was stirred (rt, 64 h). The reaction mixture was washed with H2O (4×25 mL) and brine (50 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound (2.0 g, 100%). MS (ESI): mass calculated for C10H9NO2, 175.1; m/z found, 176.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.23 (s, 1H), 7.62 (d, J=8.5, 1H), 7.21 (dd, J=3.2, 2.4, 1H), 7.18-7.15 (m, 1H), 6.87 (dd, J=8.5, 2.1, 1H), 6.55 (ddd, J=3.1, 2.0, 0.9, 1H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]/[CH:9]=[CH:10]/[CH2:11][C:12](O)=[O:13].C1(C/C=C/CC(O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)C/C=C/Cc1ccccc1Cl
Agent: O=C(O)C/C=C/Cc1ccccc1
Product: OCC/C=C/Cc1ccccc1Cl
Yield: 70 %

Procedure:
The substantially same method as described in Example 236 was conducted, except that (E)-5-(2-chlorophenyl)pent-3-enoic acid (Preparation example 302) was used instead of that (E)-5-phenylpent-3-enoic acid (Preparation example 235), to obtain the title compound (4.6 g, 70˜90%)