Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][CH:14]([C:17]([N:19]([CH3:42])[C:20]3[CH:40]=[CH:39][C:23]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[C:22]([CH3:41])[CH:21]=3)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][CH:14]([C:17]([N:19]([CH3:42])[C:20]3[CH:40]=[CH:39][C:23]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[C:22]([CH3:41])[CH:21]=3)=[O:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)C(=O)C2CCC(S(=O)(=O)c3ccc(Cl)cc3)CC2)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N(C)C(=O)C2CCC(S(=O)(=O)c3ccc(Cl)cc3)CC2)ccc1CN1CCN[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl (2S)-4-{4-[({4-[(4-chlorophenyl)sulfonyl]cyclohexyl}carbonyl)(methyl)amino]-2-methylbenzyl}-2-methylpiperazine-1-carboxylate (80.2 mg, 0.13 mmol) synthesized in (10D) in dichloromethane (1 mL), trifluoroacetic acid (10 mL) was added at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10 (v/v)), whereby the title compound was obtained as an oil (50.1 mg, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:34](=[O:36])[CH3:35])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(NC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Yield: 50.4 %

Procedure:
To a mixture of crude 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (200 mg) and triethylamine (0.130 mL, 0.933 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (0.0530 mL, 0.561 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min, diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-90% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (111 mg, 0.246 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2].[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([CH2:24][O:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[C:32]1([CH3:35])[CH:31]=[CH:30][C:29]([S:26]([OH:28])(=[O:25])=[O:27])=[CH:34][CH:33]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][O:21][CH:20]([CH2:24][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3][CH2:1][CH3:2])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Reactant: CCOc1ccccc1N
Solvent: CCOCC
Product: CCOc1ccccc1NCC1CN(Cc2ccccc2)CCO1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 95 °C

Procedure:
A mixture of 2-ethoxyaniline (14.0 g.) and 4-benzyl-2-toluene-p-sulphonyloxymethylmorpholine (18.6 g.) is stirred and heated on the steam bath (95° C.) under nitrogen for 24 hours. The mixture is cooled and ether added. The solid thus obtained is collected and crystallised from ethyl acetate to give 4-benzyl-2-(2-ethoxyanilino)methylmorpholine toluene-p-sulphonate, m.p. 127° C. The toluene sulphonate salt is converted into the corresponding dihydrochloride by basifying it with dilute sodium hydroxide solution, extracting the base into ether (3× 200 ml.), washing the ethereal extract with water and then drying it over anhydrous magnesium sulphate followed by filtration and treatment of the ethereal solution of base with ethereal hydrochloric acid solution. The 4-benzyl-2-(2-ethoxyanilino)-methylmorpholine dihydrochloride melts at 226° C. after crystallisation from methanol/ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([I:11])=[N:6]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCCC1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2C1CCCC1
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield from 5-fluoro-3-iodo-indazole and bromocyclopentane according to the procedure for Preparation 11A. The minor isomer was not isolated cleanly. 1H NMR (400 MHz, CDCl3): δ 1.69-1.76 (2H, m), 1.92-1.98 (2H, m), 2.12-2.18 (4H, m), 4.87-4.95 (1H, m), 7.08 (1H, dd, J=8.2, 2.3 Hz), 7.17 (1H, td, J=8.9, 2.4 Hz), 7.35 (1H, dd, J=9.1, 4.0 Hz). [M+H] calc'd for C12H12FIN2, 331; found 331.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.CCCCCC.[CH2:20]([O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)[CH2:21][CH2:22][CH2:23][CH3:24]>CN(P(N(C)C)(N(C)C)=O)C.O>[OH:33][CH:32]([CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:36][CH:35]=1)[CH2:34][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: C#CCCCC(=O)O
Reactant: CCCCCOc1ccc(OCC2CO2)cc1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: O
Product: CCCCCOc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A dry flask equipped with an addition funnel and a mechanical stirrer under Ar was charged with 100 ml of HMPA and 9.7 g of 5-hexynoic acid. The flask was cooled in an ice water bath and a solution of n-BuLi in hexane (118 ml, 0.189 mole) was added dropwise. The resulting reaction mixture was stirred for 1.5 hr and then a solution of 24.5 g of 2-(4-pentoxyphenoxymethyl)oxirane, the product of Example 14a, in 20 ml of HMPA was added and stirring was continued for 2 days. The reaction mixture was poured into water and extracted with Et2O three times. The ether solution was washed with aqueous NH4OH twice. The aqueous solution was acidified with HCl and extracted with Et2O. The ether solution was washed with saturated NaCl solution, dried over MgSO4. Solvent was removed to give the crude product which was recrystallized in cyclohexane to give the title compound, mp 58.0°-60.0°.
Reaction SMILES: [F:1][C:2]([F:57])([C:53]([F:56])([F:55])[F:54])[CH2:3][CH2:4][CH2:5][C:6]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[C:37]3[C:32](=[CH:33][C:34]([O:38]COC)=[CH:35][CH:36]=3)[O:31][CH2:30][C:29]2([CH3:52])[C:42]2[CH:47]=[CH:46][C:45]([O:48]COC)=[CH:44][CH:43]=2)=[CH:24][CH:23]=1)(C(OCC)=O)[C:7]([O:9]CC)=[O:8].[OH-].[K+].Cl>C(O)C.O>[OH:38][C:34]1[CH:33]=[C:32]2[C:37]([CH:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:6]([CH2:5][CH2:4][CH2:3][C:2]([F:57])([F:1])[C:53]([F:54])([F:55])[F:56])[C:7]([OH:9])=[O:8])=[CH:23][CH:24]=3)[C:29]([C:42]3[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=3)([CH3:52])[CH2:30][O:31]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)C(CCCCOc1ccc(C2c3ccc(OCOC)cc3OCC2(C)c2ccc(OCOC)cc2)cc1)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1ccc(OCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1
Yield: 121.2 %

Procedure:
To a solution of diethyl 2-(4,4,5,5,5-pentafluoropentyl)-2-(4-((3RS,4RS)-4-(3-methyl-7-(methyloxymethyloxy)-3-(4-(methyloxymethyloxy)phenyl)chroman-4-yl)phenyloxy)butyl)propane-1,3-dioate (0.552 g, 0.68 mmol) in ethanol (10 ml) was added the solution of potassium hydroxide (1.53 g, 27.23 mmol) in water (5 ml) and the mixture was stirred at refluxed overnight. After the reaction was completed, the reaction mixture was treated with 2N-HCl solution (pH=4) and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.513 g, quantitative) as a foamy oil.
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:14]([O:6][CH2:7][C@H:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC[C@@H](CO)N1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
Imidazole (4.09 g, 60 mmols) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) were added to a CH2Cl2 (85 ml) solution of (5S)-5-(hydroxymethyl)-2-pyrrolidinone (3.14 g, 27.3 mmols). Then, with the mixture being cooled with ice, a CH2Cl2 (15 ml) solution of tert-butyldimethylsilyl chloride (4.53 g, 30 mmols) was added, and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 300 g, MeOH—CHCl3 5:95 v/v) to obtain (5S)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (6.22 g, 99.5%): [α]D27+42.32 (c 1.136, CHCl3). IR νmax (film) cm−1: 3242, 1697. 1H-NMR (CDCl3)δ: 5.79 (1H, br), 3.80-3.71 (1H, m), 3.63 (1H, dd, J=9.9, 3.8 Hz), 3.44 (1H, dd, J=9.9, 7.7 Hz), 2.44-2.26 (2H, m), 2.24-2.11 (1H, m), 1.80-1.67 (1H, m), 0.89 (9H, s), 0.06 (6H, s). MS m/z: 230 (M++1), 214 (M+−15), 172 (100%). HRMS: Calculated for C10H20NO2Si: 214.1263 (M+−15). Found: 214.1240 (M+−15).
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.Cl.[CH3:27][N:28]([CH3:44])[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36](C(O)=O)=[CH:35]2.CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6]([C:36]2[NH:37][C:38]3[C:34]([CH:35]=2)=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:28]([CH3:44])[CH3:27])=[CH:40][CH:39]=3)=[O:7])[CH2:9]1
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)cc2c1
Yield: 66.8 %

Procedure:
Deprotection of 13 (260 mg, 0.72 mmol) as in Example C, the reaction of the product with the above 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (210 mg, 0.74 mmol), EDCI.HCl (345 mg, 1.80 mmol) and DMA (3 mL) gave crude material that was purified by precipitation from a CH2Cl2 solution at 20° C. with iPr2O (2×) to give 14e (237 mg, 67%), mp 224-227° C. 1H NMR [(CD3)2SO] δ 11.72 (d, J=1.5 Hz, 1 H, NH), 9.16 (s, 1 H, H-4), 8.35 (dd, J=7.2, 2.5 Hz, 1 H, H-6), 8.23 (dd, J=6.9, 2.5 Hz, 1 H, H-9), 7.79-7.71 (m, 1 H, H-7,8), 7.41 (d, J=8.9 Hz, 1 H, H-7'), 7.21-7.16 (m, 2 H, H-3',4', 6.94 (dd, J=9.0, 2.4 Hz, 1 H, H-6'), 4.93 (dd, J=10.6, 9.8 Hz, 1 H, H-2), 4.70 (dd, 10.9, 2.4 Hz, 1 H, H-2), 4.65-4.58 (m, 1 H, H-1), 4.18-4.09 (m, 2 H, CH2Cl), 4.07 (t, J=5.9 Hz, 2 H, OCH2), 2.66 (t, J=5.8 Hz, OCH2CH2), 2.24 (s, 6 H, N(CH3)2).
Reaction SMILES: [C:1]([OH:6])(=[O:5])C(C)=O.C(O[CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C.S(=O)(=O)(O)O.Cl[CH2:23]Cl>>[CH2:15]([O:14][C:10]([O:11][CH2:12][CH3:13])([CH3:23])[C:1]([OH:6])=[O:5])[CH3:16]
Reactant: CC(=O)C(=O)O
Reactant: CCOC(OCC)OCC
Reactant: ClCCl
Agent: O=S(=O)(O)O
Product: CCOC(C)(OCC)C(=O)O
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 14 mL (0.2 mol) of pyruvic acid and 80 mL of triethylorthoformate at 10° C. was added 1 mL of concentrated sulfuric acid. The resulting mixture was stirred at 5-10° C. for 1 h and then diluted with 200 mL of dichloromethane. The organic solution was washed successively with water (3×80 mL) and saturated sodium chloride solution (80 mL) and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated to give a quantitative yield of 2,2-diethoxypropionic acid as an oil. 1H NMR (CDCl3, 400 MHz): δ 1.30 (t, 6H), 1.61 (s, 3H), 3.57 (q, 4H), 8.62 (s, 1H). The acid form was quantitatively converted to its cesium salt by dissolving the acid in water (25 mL) followed by treatment with an equimolar quantity of cesium carbonate, and then lyophilization. 1H NMR (D2O, 400 MHz): δ 0.98 (t, 6H), 1.28 (s, 3H), 3.22 (q, 2H), 3.47 (q, 2H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([O:22]CC2C=CC=CC=2)[CH:19]([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:30]([CH3:32])[CH3:31])[S:14]2)[C@H:10]1[O:33]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[F:21][CH:19]([F:20])[C@H:18]([C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:30]([CH3:31])[CH3:32])[S:14]2)[C@@H:10]([OH:33])[C@@H:9]1[OH:8])[OH:22]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](OCc3ccccc3)C(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@H](O)C(F)F)O[C@@H]2S1
Reaction time: 0.13 h
Yield: 4.8 %

Procedure:
A solution of 99 (600 mg, 1 mmol) in dichloromethane (20 mL) was treated with BCl3 (10 mL, 10 mmol, 1 M in dichloromethane) for 1 hour at −78° C., then quenched with methanol (20 mL). Volatiles were distilled out to give a residue, which was dissolved into methanol (5 mL) and neutralized with Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give a mixture of the two epimers; the two epimers were separated by Prep-HPLC with the following conditions: (Agilent Prep 1200 Detecl): Column, SunFire Prep C18; mobile phase, Water with 0.05% ammonia and CH3CN, 5% CH3CN up to 40% in 8 min; Detector, 220 nm) to afford (3aR,5S,6S,7R,7aR)-5-((S)-2,2-difluoro-1-hydroxyethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a light yellow solid (14.4 mg, 5%), faster eluting isomer; (ES, m/z) [M+H]+ 299.0, 1H NMR (300 MHz, D2O) δ 6.19 (d, J=6.6 Hz, 1H), 5.71-6.09 (m, 1H), 4.15 (t, J=6.0 Hz, 1H), 3.89-3.99 (m, 2H), 3.78-3.82 (m, 1H), 3.37 (t, J=8.7 Hz, 1H), 2.89 (s, 6H); and (3aR,5S,6S,7R,7aR)-5-((R)-2,2-difluoro-1-hydroxyethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a light yellow solid (53.9 mg, 17.4%), slower eluting isomer; (ES, m/z) [M+H]+ 299.0, 1H NMR (300 MHz, D2O) δ 6.20 (d, J=6.3 Hz, 1H), 5.62-6.00 (m, 1H), 4.07 (t, J=6.0 Hz, 1H), 3.87-3.96 (m, 2H), 3.72-3.77 (m, 1H), 3.62-3.65 (m, 1H), 2.88 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[H][H].C(OCC)(=O)C.CCCCCC>C(O)C.[OH-].[NH4+].[Ni]>[NH2:5][CH2:4][C:3]1[CH:6]=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NCc1cc(C(F)(F)F)ccc1N

Procedure:
In a rocker shaker was charged 37 g (0.2 mol) of 2-amino-5-(trifluoromethyl)benzonitrile in 500 mL of ethanol and 76 mL of ammonium hydroxide. The contents were degassed/blanketed with nitrogen, 25 g of Raney nickel were added, then the shaker was pressurized with 40 psi hydrogen gas. At 15 hours TLC analysis (20/80 ethyl acetate/hexane) revealed no starting material. The contents were filtered through Celite and washed with ether and concentrated to 37 g black oil. The oil was chromatographed on a Biotage 75L cartridge with methanol/methylene chloride and ammonium hydroxide/methanol/methylene chloride to give [2-(aminomethyl)-4-(trifluoromethyl)phenyl]amine as a green oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:27]1([C:36](=O)[CH2:37][CH2:38][S:39][CH3:40])C2C=CC=CC=2N=[N:28]1.O.NN>C1COCC1.CCO>[CH3:40][S:39][CH2:38][CH2:37][C:36]1[NH:27][N:28]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: CSCCC(=O)n1nnc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NN
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CSCCc1[nH]nc(-c2ccc(C)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-phenyl-1-p-tolylethanone (2.0 g, 9.51 mmol) in THF (10 mL) was added LiHMDS (1.0 M in THF) (19.02 mL, 19.02 mmol) slowly via syringe at 0° C. After stirring for 10 min, 1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-(methylthio)propan-1-one (2.53 g, 11.41 mmol) was added in one portion. The reaction was stirred at 0° C. for 30 min before quenched with AcOH (2 mL). To the reaction were added EtOH (30 mL), hydrazine hydrate (1.428 g, 28.5 mmol), and brought to reflux for 2 h. After cooled to room temperature, the reaction was concentrated and extracted with EtOAc/H2O, washed with brine, dried over MgSO4, and purified by column chromatography to give the title compound a as clear oil (1.50 g). LCMS m/z=309.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.96 (s, 3H), 2.29 (s, 3H), 2.66 (t, J=7.71 Hz, 2H), 2.90 (t, J=7.58 Hz, 2H), 7.01-7.06 (m, 2H), 7.18-7.25 (m, 3H), 7.26-7.37 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH:10]([CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:23][Mg]I.[Cl-].[NH4+]>C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:23])([OH:15])[CH:10]([CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]I
Reactant: CC(C)(C)c1ccc2c(c1)CCC(CN1CCCCC1)C2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)CCC(CN1CCCCC1)C2(C)O
Yield: 82.4 %

Procedure:
6-Tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (4.4 g, 0.015 mol) in diethyl ether (40 ml) was added to an ethereal solution of methylmagnesium iodide [prepared from methyl iodide (1.9 ml, 0.03 mol) and magnesium (0.72 g, 0.03 mol)] at such a rate as to maintain reflux. It was refluxed for 1 hour, cooled and treated with saturated ammonium chloride solution (100 ml) and refluxed for 30 minutes. The ether was separated and the aqueous extracted with further ether, the combined extracts were dried over magnesium sulphate and evaporated to give a solid residue. Purification by column chromatography using silica gel with ethyl acetate: petroleum 60°-80°, 3:7 gave 6-tert-butyl-1-methyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-ol (3.9 g, 82% yield) a white solid melting at 113°-4°. 6-tert-butyl-1-methyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-ol (3.7 g, 0.012 mol) was refluxed in dilute sulphuric acid (50 ml, 10%) for 45 minutes. After cooling it was neutralized with sodium hydroxide, extracted with ether, dried over magnesium sulphate and evaporated under reduced pressure to give the title compound (3.5 g, 98% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([Cl:12])=[CH:5][C:3]=1[NH2:4].[ClH:13].O.OO>C(O)C>[Cl:13][C:5]1[C:6]([Cl:12])=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: Cl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: OO
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)cc([N+](=O)[O-])c(Cl)c1Cl
Temperature: 50 °C
Yield: 88 %

Procedure:
To a suspension of 2,5-dichloro-4-nitroaniline (4.0 g, 19.3 mmol) in ethanol (50 ml) was added concentrated hydrochloric acid (20 ml) and water (20 ml). The mixture was heated to 50° C. and 27.5% hydrogen peroxide (6 ml) added over 15 min. The mixture was maintained at this temperature for a further 2 h, cooled to room temperature, and the solid filtered and washed with water (2×20 ml) to give the title compound (D11) (4.1 g, 88%), MH+ 241/243.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[NH:5][C:4]([N:12]([CH3:14])[CH3:13])(N)[N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([OH:22])[C:19]([CH3:23])=[CH:18][CH:17]=1>C(O)C>[CH3:14][N:12]([CH3:13])[C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([OH:22])[CH:21]=2)[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=1
Reactant: Cc1ccc(N)cc1O
Reactant: CN(C)C1(N)N=C(Cl)c2cccn2N1
Solvent: CCO
Product: Cc1ccc(Nc2nc(N(C)C)nn3cccc23)cc1O
Temperature: 75 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of 4-chloro-2-dimethylaminopyrrolo[2,1-f][1,2,4]triazin-2-amine (50 mg, 0.26 mmol) (Tetrahedron, 3037, 52, 1996, José´Ma. Quintela, Maria J. Moreira and Carlos Peinador) in ethanol (2.5 mL) under argon was added 5-amino-o-cresol (35 mg, 0.28 mmol). The reaction mixture was stirred overnight at 75° C. Upon cooling, a solid precipitated which was recrystallized from warm ethanol to provide 52 mg (72%) of the title compound as white solid. MS: [M+H]+=284.2, ESI [M−H]−=282.1; 1H NMR (CDCl3): δ 7.52 (s, 1H), 7.13–6.98 (m, 4H), 6.58 (s, 1H), 3.15 (s, 6H), 2.19 (s, 3H).
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:9]=[CH:8][N:7]=1)(=O)C.S(Cl)(Cl)=O.[SH:22][C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C[O-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)[C:11]=1[CH3:12])[CH2:15][CH2:16][CH3:17]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCOc1ccnc(COC(C)=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 106.5 %

Procedure:
8.3 g of 2-acetoxymethyl-3-methyl-4-butoxy-pyridine was dissolved in chloroform, and 21.6 g (4 eq.) of thionyl chloride was added. The mixture was heated to reflux for one hour and then concentrated, and a residue resulting therefrom was dissolved in methanol. The solution was added in advance to 6.1 g (1 eq.) of 2-mercaptobenzimidazole, 230 mL of a 28% sodium methoxide solution, and 120 mL of methanol, and the mixture was heated to reflux for one hour. Methanol was distilled off, ice was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. Subsequently, the ethyl acetate solution was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 12.2 g of yellow crystals. 12.2 g of the crystals were recrystallized from ethyl acetate/1-hexane, to obtain 4.2 g of colorless crystals. Total yield 10.8% (purity by HPLC: 97.0%).