Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al].[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:4])[CH3:3].[H][H]>N1C2C(=CC=CC=2)C=CC=1.[Cu].[Pd].CCCCCC>[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:4])[CH3:3]
Reactant: [H][H]
Reactant: CCCCC#CCCC#CCCCCCCOC(C)=O
Agent: [Cu]
Agent: [Pd]
Agent: [Al]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCCC/C=C\CC/C=C\CCCCCCOC(C)=O

Procedure:
Into a 500 ml Parr hydrogenation flask fitted with an aluminum or copper cooling coil is placed 100 g of 7,11-hexadecadiynyl acetate, 100 ml hexane (olefin free), 1 g palladium on calcium carbonate (Lindlar catalyst) and 10 drops of synthetic quinoline. Hydrogenation is effected at 10- 20 psi and is complete when the theoretical amount of hydrogen for the partial reduction of two triple bonds is absorbed. During the hydrogenation the reaction temperature is maintained between 15°-25° to minimize cis-trans isomeration. The catalyst is then removed by filtration and the product isolated by distillation of the filtrate. bp 130°-132°/1 torr nD21 1.4592. Yield essentially quantitative. Based on IR analysis it is estimated that there is less than 5% of E isomers present.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9]2)=[N:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][CH2:11][CH:10]([N:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:9]4)=[N:6][CH:7]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc(N2CCCC(N3CCCC3)C2)nc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(N4CCCC(N5CCCC5)C4)nc3)nc2)cc1

Procedure:
Prepared according to general working method I from 5′-iodo-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (179 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30]NN.S(=O)(=O)(O)O>C(O)C>[CH3:30][N:9]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:11]=[N:10]1
Reactant: CNN
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (1.72 g) in ethanol (20 ml) was added methyl hydrazine (3.5 ml, 1.5 eq.) and concentrated sulfuric acid (0.1 ml). The reaction mixture was stirred 1 h at ambient temperature and solvent evaporated. The reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer dried magnesium sulfate, filtered and concentrated. Preparative HPLC chromatography provided the title compound (minor isomer) as a white solid (0.30 g, 17%). 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=5.4 Hz, 2 H), 8.21 (d, J=8.7 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H), 7.77 (s, 1 H), 7.66 (m, 3 H), 7.53 (m, 1H), 7.19 (d, J=8.7 Hz, 2 H), 7.11 (d, J=8.7 Hz, 2H), 7.01 (d, J=6.2 Hz, 2H) 5.40 (s, 2H), 3.69 (s, 3H); MS: (M+H m/z=393.3).
Reaction SMILES: [OH-].[K+].FC(F)(F)C([N:7]1[CH2:22][CH2:21][C:10]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12](=[O:20])[CH2:11]2)[CH2:9][CH2:8]1)=O.Cl.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>O.CO>[C:33]([N:7]1[CH2:8][CH2:9][C:10]2([C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12](=[O:20])[CH2:11]2)[CH2:21][CH2:22]1)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C1CC2(CCN(C(=O)C(F)(F)F)CC2)c2ccccc2N1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCC2(CC1)CC(=O)Nc1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
KOH (0.65 g, 11.5 mmol) in water (3.0 mL) was added to 19b (1.20 g, 3.8 mmol) in methanol (15 mL) and stirred at rt overnight. The reaction was neutralized with conc. HCl (1 mL) and then concentrated. The crude reaction mixture was evaporated from toluene to remove water. The crude amine was taken up in dichloromethane (30 mL) and triethylamine (2.5 mL, 19.2 mmol) and pivaloyl chloride (0.9 mL, 7.7 mmol) were added. This was stirred at rt for 4 h and then water was added to quench the reaction. The aqueous layer was extracted with dichloromethane (3×) and the combined organics were dried (MgSO4), filtered and evaporated to give the crude product. The crude product was purified by flash chromatography on Biotage using EtOAc/Hexanes (50-100%) to give 19c as a white solid (0.91 g, 79%). (M+H)+=301. 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (s, 1H); 7.30 (d, J=7.3 Hz, 1H); 7.22 (t, J=7.7 Hz, 1H); 7.08 (t, J=7.6 Hz, 1H); 6.78 (d, J=7.8 Hz, 1H); 4.30 (m, 2H); 3.18 (m, 2H); 2.75 (s, 2H); 1.91 (m, 2H); 1.71 (m, 2H); 1.28 (s, 9H).
Reaction SMILES: NC[C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1.[CH2:25]([N:27](C(C)C)C(C)C)C.Br[CH2:35][C:36]1[C:37]([CH2:42]Br)=[CH:38][CH:39]=[CH:40][CH:41]=1>CN(C)C=O>[Cl:22][C:21]1[C:16]2[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]3[N:11]([CH:10]=[N:9][C:8]=3[C:6]3[O:5][N:27]([CH3:25])[CH:3]([N:4]4[CH2:42][C:37]5[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH2:35]4)[N:7]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1ccccc1CBr
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1Cc2c(C3=NC(N4Cc5ccccc5C4)N(C)O3)ncn2-c2cccc(Cl)c2C1=O
Yield: 34.8 %

Procedure:
3.44 g (10 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 30 ml of N,N-dimethylformamide, 3.7 ml (22 mmol) of N-ethyldiisopropylamine and 2.9 g (11 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 6 hours. After evaporating the solvent the residue was chromatographed on 230 g of silica gel while eluting with ethyl acetate. The uniform fractions were evaporated. There were obtained 1.56 g (35%) of 7-chloro-5,6-dihydro-3-(3-isoindolin-2-yl-methyl-1,2,4-oxadiazol-5-yl)-5-methyl-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 180°-184°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([O:26][CH3:27])([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][C:21]([O:26][CH3:27])([CH:24]=[O:25])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -65 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of oxalyl chloride (4.36 ml) in dichloromethane (220 ml) was added dropwise at −70% a solution of dimethylsulfoxide (5.32 ml) in dichloromethane (20 ml), and 30 minutes later, to the mixture was added dropwise a solution of 1-(tert-butoxycarbonyl)-4-methoxy-4-piperidinemethanol (6.13 g) in dichloromethane (60 ml). The mixture was stirred around −65° C. for 1 hour. To the mixture was added triethylamine (17.4 ml), and the mixture was stirred between the temperature ranging from −60° C. to 0° C. for 2 hours. The reaction solution was washed with water and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give colorless solid of the title compound (6.32 g).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH:18]=[C:17]([CH2:19][C:20]#N)[CH:16]=[N:15]1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:30].[C:34](Cl)(=[O:36])[CH3:35]>CCO.S(=O)(=O)(O)O.O>[CH2:34]([O:36][C:20](=[O:30])[CH2:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:7]=2[CH2:6][S:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:18]=1)[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cn1cc(CC#N)cn1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cnn(Cc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-[3-tert-Butylsulfanylmethyl-4-(4-cyanomethyl-pyrazol-1-ylmethyl)-phenyl]-2,2-dimethyl-propionamide (0.080 g, 0.20 mmol) in EtOH (10 mL) was treated with sulfuric acid (10 drops) and stirred at 50° C. for 2 hours. No reaction was observed, so additional sulfuric acid (0.5 mL) was added, and the reaction was stirred at 62° C. overnight. A small amount of product was observed, so the mixture was diluted with H2O and extracted with EtOAc to isolate a mixture of starting material and product. The mixture was dissolved in EtOH (10 mL) and treated with acetyl chloride (0.29 mL, 4.0 mmol). The reaction was stirred overnight at 62° C., after which time the reaction was complete. The mixture was partitioned between EtOAc and H2O, and the organic layer was separated and purified by preparative HPLC to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[N:12]=1)[C:5]([OH:7])=[O:6].ClC1C=CC=C(C(OO)=[O:30])C=1>CC(O)=O>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=3)[N+:12]=2[O-:30])=[C:2]([Cl:1])[CH:3]=1)([OH:7])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3[n+]2[O-])c(Cl)c1
Yield: 37.5 %

Procedure:
To a solution of 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (Compound 8) (620 mg) in HOAc (8 mL) was added 3-chloroperbenzoic acid (77% pure, 1.19 g). The resultant mixture was heated at 90° C. over 3 hour. After removal of HOAc under reduced pressure, the resultant mixture was trituated with DCM and recrystallized from EtOH/water twice to afford the desired product (245 mg) as colorless solids. 1H NMR (DMSO-d6 300 MHz TMS): δ 10.49 (1H, s), 8.43 (1H, d, J=9 Hz), 8.06 (1H, d, J=3 Hz), 8.01 (1H, dd, J=9 and 3 Hz), 7.82 (1H, d, J=6 Hz), 7.69 (1H, d, J=6 Hz), 7.47 (1H, d, J=9 Hz), 7.37 (1H, dd, J=9 and 3 Hz), 7.31 (1H, d, J=3 Hz) ppm; MS (ESI): m/z 316, [M+H+].
Reaction SMILES: [CH3:1]N(C)CCOC1C=CC=C(C)C=1[N+]([O-])=O.[CH3:17][C:18]1[C:19]([N+:32]([O-])=O)=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.N1C2C(=CC=CC=2OCCN(C)C)C=C1>>[N:24]1([CH2:23][CH2:22][O:21][C:20]2[CH:29]=[CH:30][CH:31]=[C:18]3[C:19]=2[NH:32][CH:1]=[CH:17]3)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cccc(OCCN(C)C)c1[N+](=O)[O-]
Reactant: Cc1cccc(OCCN2CCCC2)c1[N+](=O)[O-]
Agent: CN(C)CCOc1cccc2cc[nH]c12
Product: c1cc(OCCN2CCCC2)c2[nH]ccc2c1

Procedure:
The following compound was prepared in a similar fashion, starting with dimethyl-[2-(3-methyl-2-nitro-phenoxy)-ethyl]-amine rather than 1-[2-(3-methyl-2-nitrophenoxy)-ethyl]-pyrrolidine: [2-(1H-indol-7-yloxy)-ethyl]-dimethyl-amine (69%), MS: 205 (M+H)+
Reaction SMILES: [OH-].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:22]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[C:27]=1[O:33][CH3:34])=[N+]=[N-]>C1COCC1.O>[Br:32][C:28]1[C:27]([O:33][CH3:34])=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH2:22]
Reactant: COc1c(Br)cccc1CN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Br)cccc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 g of potassium hydroxide (KOH) and 5.8 g of triphenyl phosphine (Ph3P) were added to a solution of 1-azidomethyl-3-bromo-2-methoxy-benzene 7 in 100 mL of THF and 10 mL of water. The mixture was stirred overnight at room temperature. The mixture was quenched with aqueous concentrated hydrochloride. After standard acid/base aqueous work up, 3.9 g of crude 3-bromo-2-methoxy-benzylamine 8 was obtained (after two steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[N:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Temperature: 110 °C
Reaction time: 36 h
Yield: 25.5 %

Procedure:
To a solution of 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol) in DMSO (3.0 mL) was added [6-(trifluoromethyl)pyridin-3-yl]boronic acid (0.078 g, 0.40 mmol), K2CO3(0.112 g, 0.81 mmol) and tetrakistriphenyl phosphine palladium (0) (0.062 g, 0.054 mmol). The reaction mass was stirred at 110° C. for 24-48 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 4-5% EA:DCM to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.38-7.48 (m, 1H), 7.61-7.63 (m, 1H), 7.88-7.99 (m, 4H), 8.01-8.17 (m, 2H), 8.41 (d, J=7.8 Hz, 1H), 9.14 (s, 1H), 12.60 (br s, 1H). MS (m/z): 435.25 (M+H)+.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[NH:12]([C:16]1[S:20][N:19]=[C:18]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:17]=1)[C:13]([NH2:15])=[NH:14].[NH3:26]>>[NH2:26][C:3]1[C:7]([NH:25][CH2:24][CH2:23][S:22][CH2:21][C:18]2[N:17]=[C:16]([NH:12][C:13]([NH2:15])=[NH:14])[S:20][N:19]=2)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: N=C(N)Nc1nc(CSCCN)ns1
Reactant: N
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)(=O)N=C2N)ns1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with an equimolar amount of 2-[(5-guanidino-1,2,4-thiadiazol-3-yl)methylthio]ethylamine and excess ammonia, the title compound is thereby produced.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]([Cl:15])([CH3:14])[CH:12]=O.[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:16]1([CH:12]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[C:11]([Cl:15])([Cl:10])[CH3:14])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CC(Cl)(Cl)C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1cccnc1)n1nnc2ccccc21

Procedure:
A suspension of nicotinamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.[NH:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:17]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]3)=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: OC1CCNC1
Reactant: ClCCCOCCc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: OC1CCN(CCCOCCc2ccc3sccc3c2)C1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 54.2 %

Procedure:
In 12 mL of N,N-dimethylformamide was dissolved 1.20 g of 5-[2-(3-chloropropoxy)ethyl]-1-benzothiophene, and 0.82 g of 3-pyrrolidinol and 1.30 g of potassium carbonate were added to the solution, after which the resulting mixture was stirred at 85° C. for 2.5 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=20:1 to 10:1) to obtain 0.78 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinol as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[OH-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>CN(C=O)C.O>[CH:23]1([N:13]2[C:14]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][S:16][C:12]2=[N:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrC1CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Temperature: 30 °C
Reaction time: 18 h
Yield: 26.6 %

Procedure:
A solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (Method C2a; 33.2 g, 114 mmol) in DMF (1 L) was treated with NaOH (690 g, 17.3 mol) and cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was stirred at 20-40° C. for 18 h, then cooled to 4° C., and treated with water (1.5 L). A conc. HCl solution was added to adjust the pH to 0, and the mixture was extracted with EtOAc (80 mL). The organic phase was washed with a 1N HCl solution (1 L), dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (500 mL) and filtered through a pad of silica gel (9×4 cm). Hexane was added to the resulting solution and volatiles were slowly removed by partial vacuum until crystals formed. The solids were collected to yield 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane as yellow crystals (10.9 g, 26%): mp 118-9° C.; TLC (5% EtOAc/hex) Rf0.34.
Reaction SMILES: N(C([O-])=O)=NC([O-])=O.[OH:9][C:10]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[CH:21](O)([CH3:23])[CH3:22].C1COCC1>C(OCC)(=O)C.O>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:10]=1[O:9][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)O
Reactant: COC(=O)c1ccc(C)cc1O
Agent: O=C([O-])N=NC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C)cc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
Disopropyl azodicarboxylate (8.7 mL, 44 mmol) is added to a stirred solution of methyl 2-hydroxy-4-methylbenzoate (4.85 g, 29.2 mmol), isopropanol (3.3 mL, 44 mmol), triphenylphosphene (11.5 g, 43.8 mmol) and THF (50 mL) at room temperature. The exothermic reaction is cooled in an ice bath and is allowed to stir overnight at room temperature. The mixture is diluted with ethyl acetate and water, and the organic phase is washed with brine and dried over MgSO4. The crude residue is purified by flash chromatography (20 to 40% EtOAc/heptane) to afford the title compound (4.95 g, 81%) as an oil. ES/MS m/e 209.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35].CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[C:34]([O:38][C:39](=[O:42])[CH2:40][NH:41][C:14]([C:13]1[CH:17]=[CH:18][C:10]([CH2:9][S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:32])([F:31])[F:33])[CH:24]=2)(=[O:22])=[O:21])=[CH:11][CH:12]=1)=[O:16])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (98 mg, 0.18 mmol), glycine t-butyl ester (36 mg, 0.27 mmol), 4-methyl morpholine (60 μl, 0.55 mmol) and EDC (53 mg, 0.27 mmol) in DMF (3 ml) was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc (2×5 ml). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (30%-100% EtOAc in hexane) to afford the title compound (92 mg, 78%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:19]=[N:20][C:21]([O:28][CH2:29][CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1.C(N(CC)C(C)C)(C)C.Cl[CH2:49][C:50]([CH3:53])([OH:52])[CH3:51].[I-].[Na+]>C(#N)C>[OH:52][C:50]([CH3:53])([CH3:51])[CH2:49][N:34]1[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][O:28][C:21]2[N:20]=[CH:19][C:18]([C:15]3[N:14]=[C:13]([C:37]#[N:38])[C:12]4[N:11]=[N:10][N:9]([CH3:8])[C:17]=4[CH:16]=3)=[CH:23][C:22]=2[C:24]([F:25])([F:26])[F:27])[CH2:32][CH2:33]1
Reactant: CC(C)(O)CCl
Reactant: Cn1nnc2c(C#N)nc(-c3cnc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Agent: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc2c(C#N)nc(-c3cnc(OCCC4CCN(CC(C)(C)O)CC4)c(C(F)(F)F)c3)cc21
Temperature: 160 °C
Yield: 31 %

Procedure:
To a solution of 1-methyl-6-(6-(2-(piperidin-4-yl)ethoxy)-5-(trifluoromethyl)-pyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile trifluoroacetate (70 mg) and N,N-diisopropylethylamine (85 mg) in acetonitrile (2 ml), 1-chloro-2-methylpropan-2-ol (48 mg) and sodium iodide (19 mg) were added and heated in microwave at 160° C. for 0.5 h. The reaction mixture was concentrated then diluted with dichloromethane and water, extracted with dichloromethane and separated by hydrophobic frits, concentrated. Purified by Strata Si column (5 g, dichloromethane:methanol=1:0, 25:1, 15:1, 12.5:1 to 10:1) then passed through Strata SCX column (1 g) to give 20.0 mg yellow amorphous as 6-(6-(2-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (31%).
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[F:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:2]3[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=3[CH3:8])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
The product (790 mg) is obtained according to the method of stage 1 of Example 4, by using 900 μL of 2-fluoro-3-methyl-nitrobenzene and 2.6 g of 4-(4-fluoro-phenoxy)-phenylamine obtained in stage 2 of Example 5 in the presence of 2.36 g of potassium tert-butanolate in 80 mL of DMSO.