Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](OCC)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:13][CH2:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cc(-c2ccccc2)on1
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A solution of ethyl 5-phenylisoxazole-3-carboxylate (5.90 g, 27 mmol) in ether (30 ml) was added dropwise to a suspension of lithium aluminium hydride in ether (20 ml). When addition was complete, the mixture was heated at reflux for 1 h then a further quantity of lithium aluminium hydride (0.25 g) was added and reflux continued for 0.5 h. The reaction was cautiously quenched with 2% sulphuric acid and the ether layer separated, dried (MgSO4) and the solvent removed under reduced pressure to yield 3-hydroxymethyl-5-phenylisoxazole (2.10 g, 12 mmol, 44%); δH (CDCl3) 3.60(1H,br,OH), 4.75(2H,s,CH2), 6.35(1H,s,CH), 7.2-7.8(5H,m,C6H5).
Reaction SMILES: CO.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.[Br:14]Br.[CH2:16]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:12][CH:11]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25]1)[CH:10]([OH:13])[C:7]1[CH:8]=[CH:9][C:4]([OH:3])=[CH:5][CH:6]=1.[BrH:14]
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: BrBr
Reactant: CCC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CO
Product: Br
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To 5 ml of methanol were added 6.0 g of 4'-hydroxypropiophenone. 6.4 Grams of bromine were added dropwise to the mixture with stirring at room temperature. The reaction liquid was stirred for an additional 10 minutes and then air was introduced thereinto at a flow rate of 200 ml/minute for 30 minutes at room temperature. To the reaction liquid were then added 7.5 g of 4-benzylpyridine and 100 ml of ethanol, and the mixture was refluxed under heating for 5 hours. The reaction mixture was treated in the same manner as described in Example 5, whereby 10.7 g (65.8%) of ifenprodil hydrobromide were obtained as white crystals.
Reaction SMILES: O1C2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].I[CH3:15].[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]>C1COCC1>[CH3:15][C:7]1([CH3:6])[C:8](=[O:11])[CH2:9][CH2:10][C:16]2([O:18][CH2:21][CH2:20][O:19]2)[CH2:17]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOC(C)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC2(CCC1=O)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (1.0 equiv.) in anhydrous THF (0.6 M) was added sodium hydride (2.0 equiv, 60% in mineral oil) at 0° C. under nitrogen. After the resulting reaction mixture was stirred at room temperature for 60 min, iodomethane (2.5 equiv.) was added. The reaction was stirred at 10° C. overnight. TLC (petroleum ether:ethyl acetate=10:1) showed that the reaction was completed. The reaction was quenched with saturated aqueous ammonium chloride solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the 7,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-one (40% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.99 (s, 4H), 2.55-2.58 (m, 2H), 1.97-2.00 (m, 2H), 1.87 (s, 2H), 1.16 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C[N:12](C)[CH2:13][CH2:14]N(C)C.[CH2:19]([Li])[CH2:20][CH2:21]C.CCCCCC>O1CCCC1>[C:13]([CH2:14][CH2:19][CH2:20][CH2:21][CH2:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)#[N:12]
Reactant: Cc1cccc2cncn12
Reactant: CN(C)CCN(C)C
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCCCCCc1cccc2cncn12
Temperature: 0 °C

Procedure:
A solution of 5-methylimidazo[1,5-a]pyridine (4.0 g) and tetramethylethylene diamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0° under nitrogen and 26.5 ml of 1.6N n-butyllithium is hexane is added dropwise maintaining the temperature below 2°. After 30 minutes this solution is transferred under nitrogen over 45 minutes to an ice-cold solution of 5-bromovalerontrile (4.86 g) in 80 ml of tetrahydrofuran. After 15 minutes the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is reextracted with 2N hydrochloric acid (3×15 ml). Basification of the aqueous phase to pH=10 with 50% sodium hydroxide, extraction with ethyl acetate (2×75 ml), drying over magnesium sulfate, evaporation and chromatography (SiO2, ethyl acetate) yields 5-(5-cyanopentyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=C[CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C(=NC=CC=3)CC2)=[N:27]C(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[N:27][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCc3ncccc32)n1
Product: CCc1nc(NC2CCc3ncccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.49, 7.67, 7.17, 5.77, 4.55, 3.21, 3.09, 2.85-2.75, 2.58, 1.97, 1.31-1.25; HRMS (FAB) calcd for C16H19BrN4+H 347.0872, found 347.0878.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH:1]([CH:11]=[CH:10][C:9]([OH:13])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C=CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: O=C(O)C=CC=Cc1ccccc1
Reaction time: 48 h

Procedure:
Styrene and acrylic acid were dissolved in benzene in a total concentration of 30% by weight. An amount of 0.2% by weight based on the total monomers of azobisisobutyronitrile was added to the solution. The mixture was sealed in a tube under a nitrogen gas, and the polymerization was carried out at 70° C. over a period of 48 hours to provide a styrene-acrylic acid copolymer.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:3][C:4]#[N:5].C(N(CC)CC)C.Cl.[C:20]([NH:24][NH2:25])([CH3:23])([CH3:22])[CH3:21]>CCO.CCOC(C)=O>[C:20]([N:24]1[C:4]([NH2:5])=[CH:3][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)NN
Reactant: N#CCC(=O)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)n1nc(-c2ccccn2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a stirred solution of 3-oxo-3-pyridin-2-yl-propionitrile (0.40 g, 2.7 mmol; CAS 54123-21-6) at r.t. in EtOH (10 ml) under an argon atmosphere were added triethylamine (1.1 ml, 8.2 mmol) and t-butylhydrazine hydrochloride (1.02 g, 8.2 mmol). The mixture was heated to reflux and stirring was continued for 2 hrs. The orange solution was cooled to r.t. The solids were filtered off. The filtrate was concentrated to leave an orange viscous oil which was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc and with CH2Cl2/MeOH 9:1. The combined organics were dried over MgSO4, filtered and concentrated. After silica gel chromatography using CH2Cl2/MeOH as gradient, the product was obtained as off-white solid (0.366 g, 62%).
Reaction SMILES: C[CH:2]([C:39]([O-:41])=[O:40])[N:3]([C:12](=[O:38])[CH:13]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH:14][C:15]([O:17][CH:18]1[CH:25]2[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2)=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O1CCOC[CH2:43]1>O>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([CH2:28][C:13]([CH3:43])([NH:14][C:15]([O:17][CH:18]2[CH:19]3[CH2:20][CH:21]4[CH2:22][CH:23]([CH2:24][CH:25]2[CH2:26]4)[CH2:27]3)=[O:16])[C:12]([N:3]([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][C:39]([OH:41])=[O:40])=[O:38])=[CH:30]1
Reactant: C1COCCO1
Reactant: CC(C(=O)[O-])N(CCc1ccccc1)C(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Solvent: O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)N(CCc1ccccc1)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl N-[α-methyl-N-[(tricyclo[3.3.1.13,7 ]dec-2-yloxycarbonyl)-DL-tryptophyl]-N-(2-phenylethyl)glycinate (285 mg, 0.5 mmol) in dioxane (10 mL) and water (5 mL) was added lithium hydroxide-1-hydrate (42 mg, 1.0 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated, acidified with dilute HCl, and extracted with ethyl acetate (2×50 mL). After drying over magnesium sulfate and concentration, flash column chromatography yielded the title compound which was crystallized from ethyl acetate and hexane to give 80 mg (29%) of white solid, mp 100°-105° C. IR (KBr) 3388 2908, 2855 1710 cm-1 ; NMR (250 MHz DMSO, 70° C.) 1.30 (3H, s), 1.1-1.58 (2H, m), 1.58-2.18 (12H, m), 2.56-2.92 (2H, m), 2.92-3.6 (4H, m), 3.6-4.26 (4H, m), 4.76 (1H, br s), 6.82-7.38 (9H, m), 7.45 (1H, d, J 7.7 Hz), 10.70 (1H, br s).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[CH:6][CH:7]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CS(O)(=O)=O.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2nnc[nH]2)ccc1Br
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Temperature: 68 °C

Procedure:
3-Bromo-2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridine (1 equiv), 3,4-dihydro-2H-pyran (2 equiv) and methanesulfonic acid (0.1 equiv) were combined in tetrahydrofuran. The reaction was heated to 68° C. for 3.5 h, cooled to room temperature, and treated with triethylamine (0.4 equiv). The reaction mixture was concentrated under reduced pressure, treated with acetonitrile and concentrated under reduced pressure at 35° C. The residue was dissolved in acetonitrile (1 volume) and water (2.25 volumes), and the solids were collected by filtration, washed with a solution of 20% acetonitrile in water and dried. The crude product was triturated with hexanes, filtered, washed with hexanes and dried to provide the desired product, as a solid. MS (ESI) m/z 324.9 [M+2]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[H-].[Na+].[F:10][C:11]([F:22])([F:21])[C:12]1[C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=[CH:14][CH:13]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH3:7][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]2[C:12]([C:11]([F:22])([F:10])[F:21])=[CH:13][CH:14]=[N:15][CH:16]=2)[O:6][N:5]=1
Reactant: O=C(Cl)c1cnccc1C(F)(F)F
Reactant: Cc1cc(N)on1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2cnccc2C(F)(F)F)on1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
5-Amino-3-methylisoxazole (147 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml), sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol) was added and subsequently, 4-trifluoromethylnicotinic acid chloride (314 mg, 1.5 mmol) was added under ice-cooling. The mixture was stirred under heating at 80° C. for 2 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by thin layer chromatography (a developing solvent: ethyl acetate/hexane=1/1) to obtain the title compound (181 mg, yield 44%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)=[O:4].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([OH:26])=[CH:21][CH:20]=2.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[O:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:16])=[CH:25]2)=[O:4]
Reactant: COC(=O)c1cn2ncnc(Cl)c2c1C
Reactant: Cc1cc2cc(O)ccc2[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.8 %

Procedure:
To a stirred solution of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (0.5 g, 2.22 inmol) and 2-methyl-5-hydroxyindole (424 mg, 2.9 mmol) under argon in acetonitrile (10.0 mL) was added triethylamine (6.65 mmol, 0.93 mL). After stirring the mixture at room temperature for 17 h. solvent was removed under vacuum and the residue was chromatographed on silica gel eluting with 20-30% ethyl acetate (gradient) in hexanes. The solvent was removed in vacuo to obtain 5-methyl-4-(2-methyl-1H-indol-5-yloxy)-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester as a white solid (0.58 g, 85%). LC/MS; (M+H)+=337.2 B. To a solution of compound A (575 mg, 1.71 mmol) in pyridine (20 mL) was added lithium iodide (17 mmol, 2.3 g). The mixture was stirred at reflux for 45 h. The mixture was allowed to cool and the pyridine was then removed in vacuo. The remaining solid material was purified by preparative HPLC. Removal of the eluent in vacuo afforded 5-methyl-4-(2-methyl-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (228 mg, 41%) as a brown solid. LC/MS; (M+H)+=323.1 C. To a solution of compound B (35 mg, 0.11 mmol) in dioxane (7 mL) was added ca. 5 mg of crushed 4 Å molecular sieves, triethylamine (0.13 mmol, 18 EL), and DPPA (0.13 mmol, 28 mL). The mixture was heated under argon at 50° C. for 6 h, followed by addition of the 3-piperidinepropanol (1.1 mmol, 156 mg) in dioxane (2.0 mL), warmed to 76° C., then allowed to stir for ca. 16 h. The reaction mixture was purified on preparative HPLC. The product obtained was then dissolved in ethyl acetate (100 mL) and washed with 30 mL of saturated aqueous sodium bicarbonate, dried, filtered and concentrated in vacuo. The oil was then chromatographed using silica gel eluting with 1% triethylamine, 10% methanol in chloroform. Removal of the solvent in vacuo afforded the title compound (9.2 mg, 18%) as an orange oil. LC/MS; (M+H)+=323.2
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:7]1[CH:6]=[C:5]2[CH:4]([Br:11])[O:3][C:1](=[O:2])[C:10]2=[CH:9][CH:8]=1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccccc21

Procedure:
A suspension of 1.34 g of phthalide and 1.78 g of N-bromo-succinimide in 100 ml of dry carbon tetrachloride is irradiated with an ultraviolet lamp for 30 minutes. The suspension becomes clear and then a precipitation of succinimide occurs. The reaction mixture is cooled and washed with cold, dilute sodium bicarbonate and water. Concentration of the carbon tetrachloride solution affords a solid, which on recrystallization from ether-hexane affords the title compound, mp 75° - 76° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=1.[C:14]([C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15].[CH2:25](N(CC)CC)C>O.C1(C)C=CC=CC=1>[C:14]([C@@H:18]1[CH2:19][CH2:20][C@H:21]([NH:24][C:2]2[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:25])=[O:10])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=2)[CH2:22][CH2:23]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: COC(=O)Cc1c(C)ncnc1Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1c(C)ncnc1N[C@H]1CC[C@@H](C(C)(C)C)CC1

Procedure:
15.2 g (71 mmol) of methyl (4-chloro-6-methylpyrimidin-5-yl)acetate, 11.0 g (71 mmol) of cis-4-tert-butylcyclohexylamine and 20.2 g (0.2 mol) of triethylamine were heated at 80° to 90° C. for 6 hours without solvent. After cooling, the mixture was taken up in water/toluene and the organic phase was dried and concentrated. In the chromatography on silica gel (petroleum ether/ethyl acetate 1:1, then ethyl acetate/methanol 9:1), 5.3 g of chloropyrimidine starting material were first of all retained and then 10.0 g (27.7% of theory) of product were obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.CO[CH:18](OC)[CH2:19][S:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:3]=1[NH:4][CH:18]=[C:19]2[S:20][CH3:21]
Reactant: COC(CSC)OC
Reactant: Nc1ccc(F)cc1Cl
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1c[nH]c2c(Cl)cc(F)cc12
Reaction time: 3 h
Yield: 46.2 %

Procedure:
Following the procedure described in J.Amer.Chem.Soc. 96 (17), 5495 (1974) 2-chloro-4-fluoroaniline (1.45 g, 10 mmole) was dissolved in methylene chloride (35 ml) and stirred vigorously at −65° C. under nitrogen while freshly prepared t-butyl hypochlorite (1.08 g, 10 mmole) dissolved in 10 ml methylene chloride was added dropwise. Ten minutes after the completion of the addition a solution of 1,1-dimethoxy-2-methylsulfanyl-ethane (1.36 g, 10 mmole) dissolved in 10 ml methylene chloride was added slowly. The reaction mixture was stirred at −65° C. for 1 h after which time, triethyl amine (1.01 g, 10 mmole) dissolved in 10 ml methylene chloride was added and the temperature was allowed to rise to room temperature. Water was added and the organic layer was separated, dried over magnesium sulfate, filtered and evaporated to dryness. The oily residue was taken up in carbon tetrachloride (35 ml) containing triethylamine (2 ml) and refluxed overnight. The solvent was removed and replaced with ether (35 ml) and stirred in a two-phase system with 12 ml of 2N HCl for about 3 h. The ether layer was then separated, washed with bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to dryness. Purification by chromatography on silica gel (1:9 ethyl acetate:hexane) afforded the pure 7-chloro-5-fluoro-3-methylsulfanyl-1H-indole (0.997 g, 46% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:12]3[N:13]=[C:14]([NH2:16])[N:15]=[C:11]3[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[N:4][N:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.[CH2:40]([N:42]=[C:43]=[O:44])[CH3:41]>C1(C)C=CC=CC=1>[CH2:40]([NH:42][C:43]([NH:16][C:14]1[N:15]=[C:11]2[CH:10]=[C:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[N:12]2[N:13]=1)=[O:44])[CH3:41]
Reactant: CCN=C=O
Reactant: Cc1nnc(-c2cc(-c3cccnc3)cc3nc(N)nn23)o1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3nnc(C)o3)n2n1
Temperature: 110 °C

Procedure:
A suspension of the product of Step 3 in toluene (20 mL) containing dibutyltin diacetate (0.1 mL) and ethyl isocyanate (0.2 mL) was heated to 110° C. for 48 h. The suspension was cooled and the precipitate was filtered and washed with toluene to give the tile compound as a solid; m.p. 318-321°. ACPI-MS Found: [M+H]+=365.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[CH2:10]=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:10]
Reactant: C=O
Reactant: COC(=O)[C@H]1CCCN1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CCCN1C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
(2R)-proline methylester (1.20 g, 10.0 mmol) was dissolve in DMF (30 mL), and formalin (37% in water, 1.12 mL, 15.0 mmol) and NaBH (OAc)3 (4.20 g, 20.0 mmol) were added portionwise. After 12 h, the reaction material was concentrated in vacuo, and the residue was diluted with NaHCO3 (30 mL). The organic material was extracted with EtOAc, and the organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=4/1) to give the title compound (1.33 g, 93.0%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:16]([N:17]=[C:5]=[O:11])[C:15]=1[CH3:21]
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1N=C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 229 %

Procedure:
A solution of triphosgene (2.25 g, 7.58 mmol) in toluene (27 mL), cooled in an ice-water bath, was treated slowly with a solution of 3-bromo-2-methylaniline (3.00 g, 16.1 mmol) and DIEA (5.6 mL, 32.2 mmol) in toluene (5.4 mL). The resulting suspension was stirred at room temperature for 2 h. The precipitate was removed by filtration and washed with EtOAc. The combined filtrates were diluted with EtOAc, washed with brine, dried and concentrated to provide 1-bromo-3-isocyanato-2-methylbenzene as a brown oil (3.68 g, 98% yield), used without purification. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, J=8.1, 0.9 Hz, 1H), 7.31 (dd, J=7.9, 0.7 Hz, 1H), 7.15 (td, J=8.0, 0.7 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=O)[CH3:34])=[CH:29][CH:28]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=1)=[CH2:34])[CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCN(CC)CC
Product: C=C(c1ccc(F)cc1)[Sn](CCCC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (1.39 mL, 10.1 mmol) in 20 mL THF at 0° C. was added butyllithium (4.02 mL, 10.0 mmol). After 10 min, tributylstannane (2.45 mL, 9.23 mmol) was added. After 10 min, the reaction mixture was cooled to −78° C. and a solution of 1-(4-fluorophenyl)ethanone (1.09 mL, 9.05 mmol) in 10 mL THF was added slowly by syringe in portions over 10 min. After 10 min, triethylamine (9.43 mL, 67.9 mmol) and methanesulfonyl chloride (2.80 mL, 36.2 mmol) was added and the bath allowed to expire overnight. The reaction mixture was treated with 50 mL hexanes and filtered, rinsing with hexanes. The filtrate was extracted with ACN, and the hexanes layer was dried over sodium sulfate, filtered, and concentrated. Purification with C-18 silica gel, eluting with DCM/ACN, gave tributyl(1-(4-fluorophenyl)vinyl)stannane as an oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.[OH-].[Na+]>ClCCl.CO>[CH3:29][C:25]1[CH:24]=[C:23]([NH:22]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: Cc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and m-toluidine in dichloromethane and subsequent treatment with sodium hydroxide solution in methanol.