Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([O-:3])=O.C[O-].[Li+].C(=O)(O)[O-].[Na+].[C:27]([C:29]1[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]2[CH:17]=[CH:18][C:6]([CH2:5][C:4]3[CH:28]=[C:27]([C:29]4[C:30]([NH2:35])=[N:31][CH:32]=[CH:33][CH:34]=4)[O:3][N:1]=3)=[CH:7][CH:8]=2)[CH:12]=1
Reactant: C#Cc1cccnc1N
Reactant: O=[N+]([O-])CCc1ccc(Oc2cccnc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3cccnc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a methanol (10.0 mL) solution of 3-(4-(2-nitro-ethyl)-phenoxy)-pyridine (819 mg, 3.35 mmol) described in Manufacturing Example 76-1-3 was added lithium methoxide (254 mg, 6.70 mmol) under nitrogen atmosphere at room temperature, which was stirred for 30 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure, and anhydrous dichloromethane (15.0 ml) and anhydrous tetrahydrofuran (7.00 mL) were added to the residue. Titanium (IV) chloride (1.18 mL, 10.7 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), and stirred for 30 minutes at room temperature. Sodium bicarbonate solution and ethyl acetate were added to the reaction mixture on an ice bath (0° C.), which was then filtered through a Celite pad. The organic layer of the filtrate was extracted with ethyl acetate, and that organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (400 mg). To a tetrahydrofuran (5.00 mL) solution of this crude product (250 mg) and 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (40.0 mg, 0.339 mmol) was added triethylamine (142 μL, 1.02 mmol) at room temperature, which was stirred for 3 hours at 60° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1), the mixture was further purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound (11.7 mg, 10.0%) as a ditrifluoracetic acid salt.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[Mg].C(OCC)(=O)CC(OCC)=O>CCOCC>[CH2:27]([O:26][C:24](=[O:25])[CH:23]([C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17])[C:22]([O:30][CH2:31][CH3:32])=[O:29])[CH3:28]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(C#N)cc2)cc1
Yield: 72 %

Procedure:
A mixture of 30 g of 2-[-4'-(4"-cyano-phenoxy)-phenoxy]-propionyl chloride and 30 ml of ether is added dropwise to a 35% etheral solution of magnesium diethyl malonate prepared from 17.6 g of diethyl malonate. The addition of the acid chloride having been completed the reaction mixture is heated to boiling for an hour and worked up as described in Example 1. Thus 30 g of the desired compound are obtained in the form of a viscous oil which solidifies on standing and melts at 42°-46° C. Yield 72%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:19][OH:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[C:34](N1C=CN=C1)(=[O:36])[CH3:35].Cl>O1CCCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([F:18])[CH:11]=3)[C:34]([CH3:35])([OH:36])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)n1ccnc1
Reactant: CSc1ccc(CC(=NO)c2ccc(Br)cc2)cc1F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C2C(c3ccc(Br)cc3)=NOC2(C)O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a solution of 1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone oxime (1.56 g, 4,42 mmol) in tetrahydrofuran (10 ml) was added dropwise 9.7 ml (9.70 mmol) of 1 M lithium N,N-diisopropylamide in tetrahydrofuran and hexane, which was prepared from N,N-diisopropylalmine and 1.6 M n-butyl lithium in hexane, over 0.5 h at −78˜−50° C. After 1 h, a solution of N-acetyl imidazole (584 mg, 5.31 mmol) in tetrahydrofuran (10 ml) was added to the mixture at the same temperature. The resulting mixture was allowed to warm up to room temperature and stirred for further 1 h. Then, the mixture was acidified with 2M hydrochloric acid (˜30 ml) and extracted with diethyl ether (150 ml). The separated organic layer was washed with saturated sodium bicarbonate (50 ml×2) and water (50 ml), dried over magnesium sulfate, and evaporated. The obtained oily residue was chromatographed on a column of silica gel (80 g) as eluting with ethyl acetate/hexane (1/4) to afford 632 mg (36%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[F:28][CH:29]1[CH2:32][N:31]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:36]3[CH2:37][CH2:38][CH:33]([N:31]4[CH2:30][CH:29]([F:28])[CH2:32]4)[CH2:34][CH2:35]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: FC1CN(C2CCNCC2)C1
Product: FC1CN(C2CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 4-(3-fluoro-azetidin-1-yl)-piperidine in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (201 mg, 47%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[CH3:24][C:25]1(C)C(C)(C)OB(C=C)O1.C(B1OC(C)(C)C(C)(C)O1)=C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH:24]=[CH2:25])[N:9]1[CH:12]=[CH:13][N:14]=[C:8]1[C:7]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[N:6]2
Reactant: OCCCNc1nc2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C=Cc1cc2c(cc1C(F)(F)F)nc(NCCCO)c1nccn12
Yield: 14 %

Procedure:
A solution of 3-(8-bromo-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol prepared as in example 52 (1 g; 2.57 mmol; 1 eq), 1,1′bis(diphenylphosphino) ferrocene)palladium dichloride. Dichloromethane complex (210 mg; 0.257 mmol; 0.1 eq), vinylboronic acid pinacol ester 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (700 μl; 4.1 mmol; 1.6 eq), potassium carbonate (1.42 g; 10.28 mmol; 4 eq) in acetonitrile (12 ml) and water (4 ml) is stirred 24 h at 65° C. under argon. The conversion being slow the reaction mixture is stirred for 3 additional days at 65° C. under argon with daily addition of 1,1′bis(diphenylphosphino) ferrocene)palladium dichloride. dichloromethane complex (105 mg; 0.129 mmol; 0.05 additional eq) and vinylboronic acid pinacol ester 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (500 μl; 2.9 mmol; 1.1 additional eq). Concentration, partition (ethyl acetate/water), extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulphate) and purification by flash chromatography on silica gel (gradient of methanol 0 to 20% in dichloromethane) followed by trituration in methanol afforded the title compound (118 mg; 0.351 mmol; 14%) as a pale yellow powder.
Reaction SMILES: C([O:5][C:6]1[C:7]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:16][CH2:15]2)=[N:8][CH:9]=[C:10]([F:12])[N:11]=1)(C)(C)C>FC(F)(F)C(O)=O>[F:12][C:10]1[NH:11][C:6](=[O:5])[C:7]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:16][CH2:15]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)Oc1nc(F)cnc1CN1CCC(C(=O)Cc2ccccc2F)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1F)C1CCN(Cc2ncc(F)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
After dissolving 122 mg of 1-[1-(3-tert-butoxy-5-fluoro-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone in 3 ml of trifluoroacetic acid, the mixture was stirred for 1.5 hours at room temperature. The reaction solution was cooled on ice, the pH was adjusted to 7 with a 5% sodium hydroxide solution, and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (97 mg, 93% yield).
Reaction SMILES: Br[C:2]1[C:3](Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])C)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C:19]2([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:29][CH2:31][CH2:3][CH2:2][CH2:7]2)=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)OC(=O)NCC1(Nc2nc(Cl)ncc2Br)CCCCC1

Procedure:
tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate K using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.18-1.54 (m, 17H) 2.23 (d, J=14.35 Hz, 2H) 3.36 (d, J=6.44 Hz, 2H) 5.82 (s, 1H) 6.93 (s, 1H) 8.22 (s, 1H). LCMS (ESI) 419 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(OCC)=O)=NC(OCC)=O.O[C:26]1[CH:42]=[CH:41][C:29]2[CH2:30][CH:31]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:32](=[O:35])[NH:33][CH2:34][C:28]=2[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:26]1[CH:42]=[CH:41][C:29]2[CH2:30][CH:31]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:32](=[O:35])[NH:33][CH2:34][C:28]=2[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COC(=O)CC1Cc2ccc(O)cc2CNC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)CC1Cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2CNC1=O
Reaction time: 18 h
Yield: 67.7 %

Procedure:
A solution of 3-[(tert-butoxycarbonyl)amino]-1-propanol (0.14 g, 0.8 mmol) and diethyl azodicarboxylate (0.13 mL, 0.8 mmole) in anhydrous DMF (2 mL) was added dropwise to a solution of methyl (±)-8-hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.10 g, 0.4 mmole) and triphenylphosphine (0.21 g, 0.8 mmol) in anhydrous DMF (1.4 mL) and dry THF (2 mL) at RT under argon. The resulting solution was stirred for 18 hr, then was concentrated under vacuum. Silica gel chromatography (1%-3% MeOH/CH2Cl2) gave the title compound (0.11 g): MS (ES) m/e 407.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[N+:21]([O-:33])[CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cccnc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2ccc[n+]([O-])c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 3-nitro-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (2.22 g) in dichloromethane (70 ml) was added m-chloroperbenzoic acid (1.81 g). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate and extracted with chloroform. The organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (8% methanol in chloroform) to give 3-nitro-2-[3-[(E)-2-(1-oxido-3-pyridyl)vinyl]phenylamino]pyridine (1.51 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]([Cl:13])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(C(=O)Cl)s1

Procedure:
In a similar apparatus to Example 1, 15.7 g (0.1 mole) of 2,4-dimethylthiazole-5carboxylic acid were suspended in 100 ml of toluene. Under heating and reflux, phosgene was blown at a rate of 1.3 l/hr for 5 hours (0.29 mole). After completion of the reaction, the residue was filtered off and the filtrate was concentrated. As a result, 7.2 g of 2,4-dimethyl-thiazole-5-carboxylic acid chloride were obtained. Its purity and yield were 96.9% an 41.0%, respectively.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a mixture of 2-piperazinone (0.46 g, 4.59 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (1.5 mL, 10.76 mmol) in CH2Cl2 (20 mL) at 0° C. was added 6-chloropyridine-3-sulfonyl chloride (0.974 g, 4.59 mmol, Organic Process Research & Development 2009, 13, 875). The resulting slurry was stirred at room temperature for 30 min and then was concentrated. The residue was mixed with saturated aqueous NaHCO3 (10 mL) and was stirred at room temperature for 1 d. The slurry was filtered, washed with water (3×5 mL), and dried under reduced pressure to give 4-((6-chloro-3-pyridinyl)sulfonyl)-2-piperazinone as a white solid (1.12 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([CH3:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH:11]([CH2:13][CH3:14])[CH3:12])=[O:9])[CH3:2].[CH3:17][C@@:18]([C:23]([NH2:25])=[O:24])([CH:20]([CH3:22])[CH3:21])[NH2:19].[S]>ClC1C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:16]2[NH:25][C:23](=[O:24])[C:18]([CH:20]([CH3:22])[CH3:21])([CH3:17])[N:19]=2)=[C:7]([CH:15]=1)[C:8]([O:10][CH:11]([CH2:13][CH3:14])[CH3:12])=[O:9])[CH3:2]
Reactant: CCc1cnc(C)c(C(=O)OC(C)CC)c1
Reactant: CC(C)[C@](C)(N)C(N)=O
Agent: [S]
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)OC(C)CC)c1
Yield: 72.4 %

Procedure:
A mixture of 2.2 g of sec-butyl 5-ethyl-2-methylnicotinate (10 mmol), 1.3 g of a-methylvalinamide (10 mmol) and 2.0 g of sulfur (62 mmol) in 2.5 g of chlorobenzene (114 wt%) is magnetically stirred at reflux temperatures for 24 hours. The reaction is cooled, diluted with methylene chloride, and filtered to remove unreacted sulfur. The filtrate is chromatographed on silica gel using 2:1 hexane-ethyl acetate as eluant to afford 2.5 g of the title product (72% yield) as a solid; recrystallization from ether-hexane gives mp 83°-87° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:19]=[C:18]([C:20]([Cl:23])([Cl:22])[Cl:21])[O:17][N:16]=2)[CH2:11][CH2:10]1)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[Cl:23][C:20]([Cl:21])([Cl:22])[C:18]1[O:17][N:16]=[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([CH2:8][NH2:7])[CH2:10][CH2:11]2)[N:19]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2noc(C(Cl)(Cl)Cl)n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(c2noc(C(Cl)(Cl)Cl)n2)CC1

Procedure:
[1-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (500 mg, 1.25 mmol) and 30% aqueous trifluoro-acetic acid (5 ml) were stirred for 24 hours at room temperature. The mixture was evaporated and lyophilised. The product contains excess of trifluoro-acetic acid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[O:10]1[C:19]2[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:10]1[C:19]2[C:14](=[C:15]([NH:20][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: Nc1cccc2c1CCCO2
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1cccc2c1CCCO2)OCC
Temperature: 100 °C

Procedure:
Bromoacetaldehyde diethyl acetal (11.8 ml) was added to a mixture of chroman-5-yl-amine (5.85 g) (prepared according to J. Heterocyclic Chem., (1973), Vol 10 (4) page 623), and potassium carbonate (10.84 g) in dry DMF (70 ml) at room temperature under N2. The mixture was heated at 100° C. for 60 h. The cooled mixture was partitioned between water (800 ml) and ether (3×200 ml). The combined organic extracts were washed with brine/water 1:1 (2×200 ml) and dried. The solvent was evaporated and the residue purified by flash column chromatography on silica. Elution with cyclohexane/ethyl acetate 6:1 gave the title compound as a pale yellow oil (8.0 g).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:44]=[C:43]([C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]4[CH:62]=[C:61]5[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]5=[O:63])=[CH:56][CH:55]=4)=[CH:50][CH:49]=3)=[O:46])[O:42][N:41]=2)=[CH:36][CH:35]=1>>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:44]=[C:43]([C:45]([NH:47][C:48]3[CH:49]=[CH:50][C:51]([C:54]4[CH:62]=[C:61]5[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([OH:67])=[O:66])[C:60]5=[O:63])=[CH:56][CH:55]=4)=[CH:52][CH:53]=3)=[O:46])[O:42][N:41]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(F)cc5)no4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(F)cc5)no4)cc3)cc2C1=O
Yield: 93 %

Procedure:
The compound of example 616 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 615.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2-:14].[Na+].CC1C=CC(C(C)C)=CC=1.Cl>CCOC(C)=O.O>[CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: [NH2-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cc2ccccc2)ccn1
Temperature: 165 °C
Reaction time: 24 h

Procedure:
A mixture of 4-benzylpyridine (14.1 mL, 88.6 mmol), sodium amide (5.71 g, 146 mmol), and p-cymene (105 mL) was heated to 165° C. After 1 d, the mixture was allowed to cool; water (30 mL) and concentrated hydrochloric acid (30 mL) were sequentially added, the aqueous layer was separated, and the organic layer was extracted with 60 mL of 2N HCl (aq). The aqueous extracts were then combined, washed with ether (50 mL), and made strongly basic with solid potassium hydroxide, during which time a brown oil separated. The oil was extracted into DCM (2×150 mL). The combined extracts were then dried over sodium sulfate, filtered, and concentrated to give a brown oil. Column chromatography (ISCO, 80 g, 50->100% EtOAc/Hex) afforded 4-benzylpyridin-2-amine as a tan solid. MS (ESI) m/z: Calculated: 184.1; Observed: 185 (M++1).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:13])[C:10](=[CH2:12])[CH3:11].[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1COCC1>[CH2:1]([NH:13][CH2:9][C:10]([CH3:12])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C=C(C)CN
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: C=C(C)CNCc1ccccc1
Reaction time: 22 h
Yield: 91.9 %

Procedure:
Add benzaldehyde (14.5 mL, 143 mmol) to a mixture of methallylamine (9.73 g, 137 mmol) and MgSO4 (15.0 g, 125 mmol) in THF (180 mL). Stir for 22 h, filter the mixture, and concentrate the filtrate. Dissolve the residue in EtOH (200 mL) and treat with NaBH4 (5.00 g, 132 mmol) in 3 portions. After 19 h, remove the solvent by rotary evaporation. Treat the residue with 1 M HCl (200 mL) then 5 M HCl (20 mL). Wash the solution with tert-butyl methyl ether (250 mL) and then treat with 5 M NaOH (50 mL) to make basic. Extract the mixture with CH2Cl2 (200 mL followed by 100 mL). Dry, filter and concentrate the organic solution to give the title compound (20.3 g, 92%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 4.84 (1H, s), 4.79 (1H, s), 3.63 (2H, s), 3.03 (2H, s), 1.69 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[C:8]2[OH:18].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:26][CH3:27].CN(C=O)C>CCOC(C)=O>[CH2:26]([O:18][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[CH:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=1)[CH3:27]
Reactant: CCOC(=O)c1cc(O)c2cccc(OC)c2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCC)c2cccc(OC)c2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a 25 mL round bottom flask were added ethyl 8-methoxy-4-hydroxynaphthalene-2-carboxylate (0.25 g, 1.02 mmol), Cs2CO3 (0.33 g, 1.02 mmol), iodoethane (0.79 g, 5.1 mmol) and DMF (4 mL). The resulting reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified on a silica gel column eluting with a gradient of 10-20% EtOAc/hexanes to give the title intermediate (0.19 g) as a light yellow solid.