Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:4]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:18]I>C1COCC1>[CH:1]1([C@H:4]([NH:7][C@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:5][O:6][CH3:18])[CH2:3][CH2:2]1
Reactant: C[C@H](N[C@H](CO)C1CC1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H](N[C@@H](C)c1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]ethanol (29.2 g, 0.143 mol) in THF (700 mL) at 0° C. was added NaH (6.29 g, 0.157 mol, 60% dispersion in mineral oil). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. Methyl iodide (20.30 g, 0.143 mol) was then added dropwise via syringe. Some warming occurred soon after the addition was complete. The temperature of the reaction mixture was controlled at ˜25° C. with a water bath containing a small amount of ice. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then slowly quenched with saturated aqueous NaHCO3 solution and was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (400 mL). The aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (5% MeOH in 1:1 ethyl acetate/hexanes) to afford (5)-1-cyclopropyl-2-methoxy-N-[(S)-1-phenylethyl]-ethanamine (26.52 g, 85% yield) as a light brown oil: [α]25D −61.5 (c 0.72, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30-7.25 (m, 4H), 7.20-7.16 (m, 1H), 3.98-3.93 (q, J=6.8 Hz, 1H), 3.50 (dd, JAB=9.5, JAX=3.5 Hz, 1H), 3.35 (s, 3H), 3.34 (dd, JBA=9.5, JBX=5.8 Hz, 1H), 1.79-1.74 (m, 2H), 1.33 (d, 6.5 Hz, 3H), 0.73-0.67 (m, 1H), 0.36-0.34 (m, 2H), 0.03-−0.06 (m, 2H); GC/MS (ESI) m/e 220.2 [(M+H)+, calcd for C14H22NO 220.2].
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:33][CH:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:31]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH2:39][CH:34]([CH:32]5[CH2:33][O:30][CH2:31]5)[CH2:35][CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: C1CC(C2COC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.105 g, 0.27 mmol), 4-oxetan-3-ylpiperidine (0.045 g, 0.32 mmol) in DCE (2 mL), trimethoxymethane (0.314 mL, 2.9 mmol) and acetic acid (0.017 mL, 0.29 mmol) was stirred for 18 h at room temperature. Sodium triacetoxyborohydride (0.101 g, 0.48 mmol) was added and the reaction mixture was stirred for 5 h at room temperature. After adding sodium triacetoxyborohydride (0.101 g, 0.48 mmol) the reaction mixture was stirred for a further 2 h and the suspension was partitioned between DCM and water. The organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM gradient 0:100 to 5:95) then (Si—PPC, acetone:EtOAc, 0:100 to 70:30) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 314 as an off-white solid (0.048 g, 35%). LCMS (Method G): RT=5.92 min, [M+H]+ 517.3. 1H NMR (CDCl3, 400 MHz) δ 8.03-7.99 (m, 1 H); 7.78-7.74 (m, 1H); 7.29-7.25 (m, 2 H); 4.76 (dd, J=7.9, 6.2 Hz, 2 H); 4.46 (t, J=6.2 Hz, 2 H); 4.44-4.35 (m, 4 H); 3.90-3.84 (m, 7 H); 3.78-3.73 (m, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 2.95-2.91 (m, 2H); 2.79-2.71 (m, 1 H); 2.21-2.17 (m, 2 H); 1.81-1.50 (m, 4 H); 1.49-1.41 (t, J=7.5 Hz, 3H); 1.21-1.15 (m, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:28]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:9])=[O:10])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3cccc(Cl)c3)s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(C(=O)c3ccccc3)S(=O)(=O)c3cccc(Cl)c3)s2)c1

Procedure:
In analogy to example 6, 3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (example 7, step 2) was reacted with benzoyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-benzoyl-3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 563.2 ([M+NH4]+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].C([O:13][CH2:14][CH3:15])(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:5][C@H:1]1[CH2:3][CH2:15][C@H:14]([OH:13])[CH2:2]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dissolve 2.5 g (24.5 mmol) of cis/trans-cyclopentanediol in 5 ml of THF and, at 0° C., add 16.3 ml (16.3 mmol) of phosphazene base P4-t-Bu (approx. 1M solution in hexane). After 10 min, add the resulting solution dropwise to an ice-cooled solution of 4.77 g (24.5 mmol) of bromoacetic acid tert-butyl ester. After the end of the addition, warm to RT and stir the mixture overnight. Remove fractions of the THF under reduced pressure, dilute with ethyl acetate and wash successively with 1N hydrochloric acid, pH 7 buffer solution and satd. sodium chloride solution, dry over sodium sulphate and concentrate under reduced pressure. From the residue, isolate the product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→2:1). 631.4 mg (10.7% of theory) of the target compound are obtained as a cis/trans mixture.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.Cl.[CH3:19][NH:20][CH3:21].[CH3:22][Si](C)(C)[Cl:24].O>C(O)(=O)C.CC(=O)CC>[ClH:24].[CH3:19][N:20]([CH2:22][CH:13]1[CH2:14][CH:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11][C:12]1=[O:15])[CH3:21]
Reactant: O=C1CCC(CCc2ccccc2)CC1
Reactant: CNC
Reactant: C[Si](C)(C)Cl
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCC(C)=O
Product: CN(C)CC1CC(CCc2ccccc2)CCC1=O
Temperature: 105 °C
Yield: 58 %

Procedure:
20.2 g (0.1 mole) of compound (47), 1.5 g (0.05 mole) paraformaldehyde and 4.07 g (0.05 mole) dimethylamine hydrochloride were dissolved in 40 ml acetic acid and heated in a bath at 105° C. for 20 minutes with stirring. The acetic acid was subsequently distilled off under vacuum, and the residue was dissolved in 100 ml water and extracted with ether. The aqueous phase was adjusted to a pH of 11 with aqueous sodium hydroxide solution and the Mannich base was extracted with dichloromethane. After drying and removal of the solvent by distillation, 17.5 g of the base of compound (47) were obtained, and were taken up in 2-butanone. 17.2 g of compound (48) were obtained in a yield of 58% theoretical by the subsequent addition of trimethylchlorosilane/water.
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH2:33][O:34][CH3:35])[C:26]([CH3:36])=[CH:25][C:24]=1[SH:37])([CH3:22])([CH3:21])[CH3:20]>C(Cl)C(Cl)Cl.CCOC(C)=O>[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][CH2:33][O:34][CH3:35])[C:26]([CH3:36])=[CH:25][C:24]=1[S:37][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: COCOCCOc1cc(C(C)(C)C)c(S)cc1C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCC(Cl)Cl
Product: COCOCCOc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Reaction time: 13 h

Procedure:
A solution of tosyl bromide (21.0 g; 89.32 mmol), 50 mL of trichloroethane and 20 mL of NEt3 was cooled to 0° C. To this solution was added slowly a solution of 12.4 mmol of 2-tert-butyl-4-(2-methoxymethoxy-ethoxy)-5-methyl-benzenethiol (prepared in Example AAAA) in 100 mL of trichloroethane. After 13 hours, the reaction mixture was diluted with EtOAc and washed with brine. The product was purified by flash silica gel chromatography, eluting with EtOAc:hexane (5:95, then switching to 3:7).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1.[CH2:30](N(CC)CC)C>C(O)C>[NH2:3][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:25]3[CH:26]=[CH:27][N:28]=[C:23]([Cl:22])[N:24]=3)[CH2:18][CH2:17]2)[CH:30]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Clc1ccnc(Cl)n1
Reactant: CCN(CC)CC
Solvent: CCO
Product: COc1cc2nc(N3CCN(c4ccnc(Cl)n4)CC3)cc(N)c2cc1OC

Procedure:
4-Amino-6,7-dimethoxy-2-piperazino-quinazoline (30.0 g, 0.104 mole), 2,4-dichloropyrimidine (17.3 g, 0.117 mole) and triethylamine (20.5 g, 0.203 mole) in ethanol (1200 ml) were heated at reflux for three hours. The solid which separated on cooling was filtered, slurried in hot isopropanol (500 ml), filtered and washed with hot methanol. The product was partitioned between 5% by volume methanol in methylene chloride and 10% (w/w) aqueous sodium carbonate solution, the organic layer separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The resulting solid was slurried in hot isopropanol, filtered and washed with hot isopropanol to afford 20 g. of the title compound, m.p. 266° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[Cl-].[CH3:6][C:7](C)=[O:8].[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH2:13]>O>[C:7]([NH:3][C:2]([NH:13][C:12]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:11]=1[CH3:10])=[S:1])(=[O:8])[CH3:6]
Reactant: N#C[S-]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)NC(=S)Nc1cc([N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a reactor, introduce ammonium thiocyanate (25 kg, 328.43 mol), acetyle chloride (24 kg, 337.53 mol), acetone (225 L) and 2-methyl-5-nitroaniline (Int1) (42 kg, 276.04 mol). Temperature was maintained at 25±10° C. for approximately 4 hours. Water (413 L) was added and reaction mixture was stirred for approximately 1 hour. The precipitate filtered, washed with water and diisopropylether. The product was then dried in a tray drier at 45-50° C.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:65][N:56]4[CH2:57][CH2:58][C:59]5[C:64]([C@@H:55]4[CH2:54]3)=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CO.O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:65][N:56]4[CH2:57][CH2:58][C:59]5[C:64]([C@@H:55]4[CH2:54]3)=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4c5ccccc5CCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4c5ccccc5CCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 85.5 %

Procedure:
A solution of 0.134 g of Cis-2-butyl-6-(1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 2.5 ml of methanol and 0.5 ml of tetrahydrofuran is heated at reflux for 18 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 chloroform-methanol to give 0.082 g of the desired product as a solid. FAB mass spec 610 (M+H).
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl.[O-:20][C:21]#[N:22].[Na+].O1CCCC1>O>[C:21]([N:2]1[CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]3[CH:16]=[CH:17][CH:18]=[C:7]3[CH:6]2[CH2:1]1)(=[O:20])[NH2:22]
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the mixture of 100 mg of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine, 1 ml of N hydrochloric acid and 10 ml of water, the solution of 54.5 mg of sodium cyanate in 2 ml of water is added while stirring followed by 2 ml of tetrahydrofuran. After stirring overnight at room temperature, it is extracted with methylene chloride, the extract washed with saturated aqueous sodium carbonate, dried and evaporated, to yield the 2-carbamoyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine melting at 175°-177°.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][C:24](OCC)=[O:25])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.Cl>CCCCCC.O1CCCC1>[O:25]=[C:24]([CH2:23][O:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[NH:13][CH:14]=[CH:15]2)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)COc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1ccc2[nH]ccc2c1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl-lithium (21.8ml. of a 2.92M solution in hexane) was added to a solution of dimethyl methylphosphonate (6.2g.) in dry tetrahydrofuran (50ml.) at -78°C. in an atmosphere of argon. After 10 minutes, a solution of ethyl 5-indolyloxyacetate (5.5g.) in dry tetrahydrofuran (50ml.) was added dropwise, and the mixture was stirred for 2 hours at -78°C. The reaction mixture was poured into 2N hydrochloric acid and stirred vigorously for 5 minutes, then the solvents were evaporated under reduced pressure. The residue was shaken with a mixture of ethyl acetate and water, and the organic phase was separated and washed with brine. The solution was dried, the solvents were evaporated and the residue was chromatographed on a column of silica gel MFC (250 g.)using methylene dichloride : ethyl acetate mixtures as eluant, to give dimethyl [2-oxo-3-(indol-5yloxy)propyl]phosphonate as an oil, RF = 0.3 (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][S:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCSc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1ccncc1
Temperature: 90 °C
Yield: 2.8 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 4-(2-chloroethylthio)pyridine hydrochloride (252 mg, 1.2 mmol) and potassium carbonate (454 mg, 3.3 mmol) in NMP (30 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol mixtures (100/0 increasing to 75/25) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)quinazoline (13 mg, 3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CS(C)=O>[C:12](/[C:11](/[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:14]\[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:19][CH:20]=1)#[N:13]
Reactant: CCOC(=O)CCCCCCBr
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Compound 1 (200 mg) was dissolved in dimethyl sulfoxide, and anhydrous potassium carbonate was added to the resultant solution, followed by stirring at room temperature for one hour. Thereafter, ethyl 7-bromoheptanoate (169 mg) was added to the resultant mixture, and the mixture was stirred. The potassium carbonate was separated through filtration, and the resultant filtrate was poured into ice water. Hydrochloric acid was added to the resultant mixture so as to adjust the pH to 3, and then the mixture was subjected to extraction with chloroform twice. The resultant chloroform layer was washed with brine, and then dried over anhydrous sodium sulfate. The sodium sulfate was separated through filtration, and the resultant filtrate was concentrated to dryness under reduced pressure, followed by recrystallization, to thereby produce the target product (223 mg, yield: 72%).
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([O:18]CC)=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+]>O>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([OH:18])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (2.8 g.) and ethanol (10 ml.) was mixed with a solution of sodium hydroxide (0.54 g.) in water (20 ml.), and the mixture was stirred for 1 hour at room temperature. After the reaction, a small amount of ethanol was distilled off. The remaining reaction mixture was washed with diethyl ether and then the aqueous layer was separated therefrom. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid and then the ethyl acetate layer was separated therefrom. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. The solvent was distilled off from the ethyl acetate layer to give yellow brown powder of 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (1.75 g.).
Reaction SMILES: [CH:1]1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:25]1(C2C=CC(C=O)=CC=2)CCC1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:22])[F:21])[CH:13]=3)=[CH:23][CH:24]=2)[CH2:3][CH2:2][CH2:25]1
Reactant: O=Cc1ccc(C2CCC2)cc1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)c1cccc(CCNCc2ccc(C3CCC3)cc2)c1

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 180 mg of 4-cyclobutyl-benzaldehyde (1.23 mmol) (described in example S113), 213 mg of 2-(3-trifluoromethylphenyl)-ethylamine (1.23 mmol) and 64 mg of sodium borohydride (1.69 mmol). The isolated yellow oil (343 mg, 92%) was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.85 (m, 1H), 1.92-2.21 (m, 3H), 2.33 (m, 2H), 2.89 (m, 4H), 3.53 (quint, J=9 Hz, 1H), 3.78 (s, 2H), 7.19 (m, 4H), 7.39 (m, 2H), 7.46 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[OH-].[NH4+:16]>O1CCCC1>[NH2:16][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: [NH4+]
Reactant: CON(C)C(=O)c1ccc(Cl)nc1Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(Cl)nc1N
Yield: 8 %

Procedure:
2,6-Dichloro-N-methoxy-N-methyl-nicotinamide (202.4 mg, 0.8610 mmol, Example 1) and concentrated ammonium hydroxide (1.8 mL, 29.4%, Fisher) in tetrahydrofuran (2.5 mL) were heated to 155° C. in the microwave for 2 hr. The reaction mixture was concentrated and the residue was purified on silica gel with hexanes/ethyl acetate to give 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (14.3 mg, 8% yield). HRMS, observed: 215.0463, Calcd for M+: 215.0462.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NN.CCOC(C)=O>CCO.O.[Ni]>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To 1-(4-tert-butylbenzyl)-5-nitro-1H-indole (1.00 g, 3.24 mmol) in EtOH (35 ml) at ambient temperature under a nitrogen atmosphere was added hydrazine (2.0 g, 62.5 mmol) and Raney-Ni (0.20 g of a 50% slurry in H2O). The yellow mixture was stirred at 45° C. for 1 hr. The mixture was cooled to room temperature and filtered through a celite pad (1×4.25 cm). The pad was washed with EtOH (10 ml) and concentrated in vacuo to afford a dark yellow powder. Gradient SiO2 chromatography (Hex:EtOAc) afforded 1-(4-tert-butylbenzyl)-5-amino-1H-indole as a yellow powder (0.87 g, 96% yield): MS (ESI) m/z 279.
Reaction SMILES: [C:1]1([CH2:7]N2C3C=CC=CC=3N=N2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=NC2C=CC=CC=2)=[CH:21][CH:20]=1>CO>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: c1ccc(Cn2nnc3ccccc32)cc1
Reactant: COc1ccc(C=Nc2ccccc2)cc1
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)cc1
Yield: 67 %

Procedure:
Procedure similar to that of Example 16 using [phenylmethyl]-1H-benzotriazole (10 mmol) and N-[(4-methoxyphenyl)methylene]benzenamine (10 mmol): 67% yield: mp 57°-58° C. (MeOH) (lit.1 58°-60° C.); 1H NMR (300 MHz, CDCl3) δ3.84 (s, 3H, OCH3), 6.89 (d, 1.9H, 2H, C(3 and 5)H), 7.30-7.38 (m, 3H), 7.45-7.54 (m, 4H).