Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:23]2[CH2:24][CH2:25][CH:20]([NH2:19])[CH2:21][CH2:22]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCC(N)CC2)nc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6-chloronicotinic acid ethyl ester (4.27 g, 23 mmol) was dissolved in DMF (30 ml), and potassium carbonate (4.77 g, 35 mmol) and 4-aminopiperidine (2.76 g, 28 mmol) were added thereto, followed by stirring at 80° C. for 3 hours and at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure, thereby obtaining 6-(4-aminopiperidin-1-yl)nicotinic acid ethyl ester (4.17 g, 73%) as a pale brown oil.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:16]1([N:22]2[C:34]3[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:5]3[CH:14]=[CH:15][C:2]([C:31]4[CH:32]=[CH:33][C:34]5[N:22]([C:16]6[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=6)[C:23]6[C:28]([C:29]=5[CH:30]=4)=[CH:27][CH:26]=[CH:25][CH:24]=6)=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: Brc1ccc2oc3ccc(Br)cc3c2c1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc2oc3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3c2c1
Temperature: 90 °C
Yield: 55 %

Procedure:
A mixture of 2,8-dibromodibenzo[b,d]furan (2.868 g, 10 mmol), (9-phenyl-9H-carbazol-3-yl)boronic acid (3.26 g, 10 mmol), Pd(PPh3)4 (0.30 g, 0.26 mmol) and potassium carbonate (4.1 g, 30 mmol) in dioxane/water (50 mL/10 mL) was degassed and heated at about 90° C. overnight. The resulting mixture was worked up with ethyl acetate/brine, dried over Na2SO4, purified by flash column (hexanes to hexanes/ethyl acetate 40:1). The desired fraction was collected and concentrated, filtration and dried in air to give a white solid (2.70 g, in 55% yield).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9]/[C:8]/2=[N:13]\[CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.CC(=O)OCC>[O:27]1[C:19]2[CH:18]=[CH:17][C:22](/[CH:23]=[C:10]3/[C:11](=[O:12])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)/[C:8](=[N:13]/[CH:14]([CH3:16])[CH3:15])/[S:9]/3)=[CH:21][C:20]=2[O:25][CH2:26]1
Reactant: CC(C)/N=C1\SCC(=O)N1c1ccccc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)/N=C1\S/C(=C\c2ccc3c(c2)OCO3)C(=O)N1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-phenyl-2-[(Z)-isopropylimino]-thiazolidin-4-one (150 mg, 0.64 mmol), piperonal (192 mg, 1.28 mmol) and sodium acetate (105 mg, 1.28 mmol) in acetic acid (3 mL) is stirred at 110° C. for 4 h. The dark yellow to brown solution is cooled to rt, diluted with EA (75 mL), washed with sat. aq. NaHCO3, followed by water, and evaporated. The crude product is purified by crystallisation from a small amount of methanol (approx. 5 mL) to give 5-benzo[1,3]dioxol-5-ylmeth-(Z)-ylidene-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](N(C)C)=[CH:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.Cl.C1C[O:20]CC1>>[F:1][C:2]1[C:10]2[S:9][C:8](=[O:20])[CH2:7][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COc1ccc(F)c2sc(N(C)C)cc12
Agent: Cl
Product: COc1ccc(F)c2c1CC(=O)S2
Temperature: 80 °C
Yield: 84 %

Procedure:
To a solution of N-(7-fluoro-4-methoxy-1-benzothien-2-yl)-N,N-dimethylamine (1.73 g, 7.7 mmol) in THF (25 mL) was added aqueous hydrochloric acid (1 N, 25 mL) and this was heated to 80° C. for 3 h. After cooling to room temperature then extracted with ether (100 mL), dried (MgSO4) and the solvent evaporated in vacuo to give a yellow solid. The residue was purified by flash chromatography in 5% ethyl acetate in hexane to give (1.3 g, 84%) of the title compound; δH (300 MHz, CHCl3) 6.97-6.87 (1H, m, ArH), 6.62-6.55 (1H, m, ArH), 3.91 (2H, s, CH2) and 3.85 (3H, s, OCH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[BrH:20]>CS(C)=O.O>[NH2:1][C:2]1[C:7]([Br:20])=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: COc1cc(N)c(C(=O)c2ccccc2)cc1OC
Reactant: Br
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C(=O)c2ccccc2)c(N)c(Br)c1OC
Temperature: 60 °C
Yield: 65 %

Procedure:
To a solution of 900 mg (3.5 mmol) of (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa) in 60 ml of DMSO, add dropwise at 0° C. 15 g of HBr 40% by weight in water. Heat at 60° C. for 24 hours. Add 400 ml of H2O and extract four times with 200 ml of AcOEt; dry on MgSO4, evaporate the AcOEt and purify by silica chromatography (AcOEt 1/hexane 4). Yield: 65%. 1H-NMR (CDCl3, 300 MHz): d 3.67 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 6.59 (s, 2H, NH2), 7.06 (s, 1H Ar), 7.47–7.65 (m, 5H Ar). Mass: (M+H)+=335.98+337.98.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[ClH:13].[CH3:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: Cc1cnccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cnccc1C(=O)Cl
Product: Cl

Procedure:
To a suspension of 3-methylisonicotinic acid (0.676 g) in toluene was added thionyl chloride (0.5 mL), and the reaction mixture was heated under reflux 70 min. The resulting solution was decanted from a gummy residue on the bottom of the reaction flask, evaporated and further dried under high vacuum to afford 3-methylisonicotinoyl chloride hydrochloride which was used for the acylation without further purification.
Reaction SMILES: [N+:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[N:12]=[CH:13][S:14][CH:15]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:1][C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[N:12]=[CH:13][S:14][CH:15]=1
Reactant: N#Cc1csc([N+](=O)[O-])c1-c1cscn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1csc(N)c1-c1cscn1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
To a solution of 5-nitro-4-(thiazol-4-yl)thiophene-3-carbonitrile (0.071 g, 0.31 mmol) in ethyl acetate (3 mL) was added tin (II) chloride dihydrate (0.29 g, 1.27 mmol). The reaction mixture was heated in an oil bath set at 70° C. under condenser. After 20 min. the mixture was cooled to RT and concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 5-amino-4-(thiazol-4-yl)thiophene-3-carbonitrile (24 mgs, 38%) Retention time (min)=1.837, method [4], MS (ESI) 208.0 (M+H).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N:24]1([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([N+:40]([O-])=O)[CH:34]=3)[N:29]=2)[CH2:27][CH2:26][CH2:25]1>ClCCl.N1C=CC=CC=1>[N:24]1([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH:40][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:12])[CH:34]=3)[N:29]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1ccc(-c2noc(N3CCC3)n2)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(N3CCC3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (71 mg, 0.39 mmol) in anhydrous dichloromethane (2 mL) was added dropwise oxalyl chloride (173 uL, 1.98 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was concentrated. A stirring mixture of the acid chloride and 5-(azetidin-1-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (109) (85 mg, 0.29 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 30 minutes. The crude product was purified on silica gel using 10% MeOH in dichloromethane to give N-(5-(5-(azetidin-1-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F77). 1H NMR (400 MHz, CD2Cl2) δ 10.10 (s, 1H), 9.51-9.48 (m, 1H), 8.65 (s, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 1H), 7.71 (dd, J=1.6, 7.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.27-7.24 (m, 1H), 4.26-4.22 (m, 4H), 2.48-2.40 (m, 2H), 2.34 (s, 3H). MS m/z 374.15 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14](OCC)=[O:15])[N:10]=2)=[CH:5][CH:4]=1)#[N:2].O1CCCC1.[BH4-].[Na+].O>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][OH:15])[N:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1noc(-c2ccc(C#N)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2nc(CO)no2)cc1
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 5-(4-cyanophenyl)-3-ethoxycarbonyl-1,2,4-oxadiazole (5.0 g) in methanol (50 ml)--tetrahydrofuran (50 ml) was added sodium borohydride (0.93 g) at 0° C. After stirring at 5°-10° C. for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 5-(4-cyanophenyl)-3-hydroxymethyl-1,2,4-oxadiazole (4.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1)\[CH3:7])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:18])([F:19])[F:17])[CH:10]=1)\[CH2:7][Br:21])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(OC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(OC(F)(F)F)c1
Yield: 29.5 %

Procedure:
To a stirred mixture of (E)-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (9.87 g, 0.034 mol) in carbon tetrachloride (60 mL) under a nitrogen atmosphere was added N-bromosuccinimide (9.08 g, 0.051 mol) and benzoyl peroxide in water (75%, 1.09 g, 0.003 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-trifluoromethoxy-phenoxy)-but-2-enoic acid ethyl ester (3.70 g, 29%) as a yellow oil.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[S:19][CH:18]=[N:17][C:16]=1[C:20]1[N:32]([CH3:33])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:22]2[N:21]=1)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:15]1[S:19][CH:18]=[N:17][C:16]=1[C:20]1[N:32]([CH3:33])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]2[N:21]=1)(=[O:38])=[O:36])[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1scnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1scnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.81 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.56 g of 2-(5-ethylthiothiazol-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 10 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 5 hours and then allowed to stand overnight. A 10% aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 0.6 g of 2-(5-ethylsulfonylthiazol-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (22)).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20](=O)[CH2:21][CH2:22][C:23]=1[CH3:24])(=[O:11])=[O:10].[CH2:27]1COCC1.[Li]C.C([O-])(O)=O.[Na+]>O>[CH3:24][C:23]1[CH2:22][CH:21]=[C:20]([CH3:27])[C:19]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:26])(=[O:11])=[O:10]
Reactant: CC1=C(c2ccccc2NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)CC1
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: O
Product: CC1=CCC(C)=C1c1ccccc1NS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
0.645 g (1.746 mmol) of 2-(2-(2-mesitylenesulfonyl)aminophenyl)-3-methyl-2-cyclopenten-1-one and 12 mL of THF were loaded to a 50 mL flask, and then 2.30 mL (3.677 mmol) of MeLi (1.6 M in diethyl ether) was added thereto at −78° C. and stirred at the same temperature for two hours. The reaction product was stirred for 2 hours while the temperature was slowly raised. 10 mL of distilled water was added to the resultant reaction product and the THF contained therein was removed using a rotary vacuum evaporator. 10 mL of E.A and 5 mL of 2 N HCl were added to the reaction product from which the THF had been removed and strongly stirred for 3 minutes. Subsequently, the organic layer was collected from the stirred reaction product. 5 mL of E.A was twice added to the aqueous layer to obtain the organic layer. The collected organic layer was neutralized using 5 mL of NaHCO3 and dried over MgSO4 to remove water contained therein. The solvent contained in the dried product was removed using a rotary vacuum evaporator. The product was filtered using a column chromatography (hexane:E.A=10:1) (0.550 g, 88%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13](OC)=[O:14])[CH:8]=[CH:7][C:6]=1[CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1>C(O)C>[Cl:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([NH:2][NH2:3])=[O:14])[CH:8]=[CH:7][C:6]=1[C@H:18]1[CH2:23][CH2:22][C@H:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]1
Reactant: CCOC(=O)C(C)C1CCC(c2ccc(NC(=O)C(=O)OC)cc2Cl)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of hydrazine hydrate (86 mg, 1.73 mmol) in ethanol (1 mL) was added dropwise to a stirred solution of ethyl 2-[4-(2-chloro-4-{[methoxy(oxo)acetyl]amino}phenyl)cyclo-hexyl]propanoate (0.58 g, 1.44 mmol) in ethanol (14 mL) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered to leave a solid, which was washed with ethanol to give the title compound (Intermediate 106) (0.45 g, 81%) as a white solid; 1H NMR δ 1.14 (3H, d), 1.16-1.28 (2H, m), 1.27 (3H, t), 1.4-1.58 (2H, m), 1.6-1.7 (1H, m), 1.71-1.93 (4H, m), 2.29-2.39 (1H, m), 2.82-2.94 (1H, m), 4.15 (2H, dq), 4.7 (2H, s), 7.4 (1H, d), 7.8 (1H, dd), 8.01 (1H, d), 10.4 (1H, s), 10.8 (1H, s); MS m/e MH+ 396.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[C:22][CH2:23][CH3:24]>C(Cl)Cl.C(#N)C>[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:11][C:6]2([C:4]([O:3][CH3:2])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[C:22]#[C:23][CH3:24]
Reactant: COC(=O)C1(N)CCCC1
Reactant: CCC#COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)OC)CCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred suspension of methyl-1-amino-1-cyclopentane carboxylate hydrochloride (15 g, 84.0 mmol) and N,N-diisopropylethylamine in methylene chloride (200 mL) and acetonitrile (50 mL), 4-butynyloxyphenylsulfonylchloride (24.7 g, 100 mmol) was slowly added at room temperature. Reaction mixture was stirred for 16 hrs and evaporated to dryness. It was extracted with chloroform, washed well with water and dried over anhydrous MgSO4. Chloroform layer was filtered and concentrated. The product was crystallized from a mixture acetone:hexane (1:1) to give methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclopentane carboxylate as white crystals, 26.8 g (91%), mp 81-3° C. Electrospray Mass Spec 352 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)(=O)=O.[CH2:20]([NH2:23])[C:21]#[CH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:15]1[CH:16]=[CH:17][C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][NH:23][CH2:20][C:21]#[CH:22])[CH:19]=[CH:18][C:14]1=2
Reactant: C#CCN
Reactant: CS(=O)(=O)OCCOCCc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCNCCOCCc1ccc2sccc2c1
Temperature: 80 °C

Procedure:
In 15 mL of N,N-dimethylformamide is dissolved 3.00 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-ethyl methanesulfonate, to which are added 1.40 mL of propargylamine and 2.76 g of potassium carbonate. The mixture is heated at 80° C. for 3 hours. The reaction mixture is introduced into a mixture of water and ethyl acetate, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=30:1 to 20:1) to obtain 1.63 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-(2-propynyl)amine as an oily product.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1)=[O:4].[Cl:20]C(Cl)CCl.[H][H].Cl.CO>CO.O=[Pt]=O>[CH3:1][NH:2][C:3]([CH:5]1[NH:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:6]1)=[O:4].[ClH:20]
Reactant: [H][H]
Reactant: ClCC(Cl)Cl
Reactant: CNC(=O)c1ccc(CCC(=O)OC(C)(C)C)cn1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CNC(=O)C1CCC(CCC(=O)OC(C)(C)C)CN1
Reaction time: 8 h
Yield: 111.6 %

Procedure:
A mixture of tert-butyl 3-(6-(methylcarbamoyl)pyridin-3-yl)propanoate (2.16 g, 8.18 mmol), PtO2 (0.40 g) and 1,1,2-trichloroethane (1.0 mL, 12.4 mmol) in methanol (50 mL) was placed in Parr reactor under 70 psi hydrogen atmosphere for 3.5 days. To the mixture was added 1.25 N HCl/MeOH (6 mL, 7.5 mmol) and the reaction was allowed to continue overnight. The reaction was filtered and evaporated to dryness to give tert-butyl 3-(6-(methylcarbamoyl)piperidin-3-yl)propanoate/HCl salt as a foamy solid (2.80 g). LCMS (+APCI) 271 (M+). The solid give tert-butyl 3-(6-(methylcarbamoyl)piperidin-3-yl)propanoate/HCl was mixed with dichloromethane (100 mL) at 0° C. and to this mixture was added DIPEA (diisopropylethylamine) (6.37 mL) and trifluoroacetic anhydride (3.44 g, 16.4 mmol) with stirring for 30 min. The mixture was warmed to room temperature, stirred for 30 min and evaporated to dryness. The crude was neutralized with a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate. Evaporation gave tert-butyl 3-(6-(methylcarbamoyl)-1-(2,2,2-trifluoroacetyl)piperidin-3-yl)propanoate as an oil that was purified by silica chromatography eluting with a gradient of 5% to 100% EtOAc/Hex then 0% to 10% MeOH/EtOAc to give 0.84 g of the ester as an oil. LCMS (+APCI) 367 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:24].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:4][C:3]=1[CH2:24][Br:25]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(c1ccc(C#N)cc1)c1ccc(Br)c(CBr)c1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl N-(4-bromo-3-methylphenyl)-N-(4-cyanophenyl)carbamate (6.18 g, 15.9 mmol), N-bromosuccinimide (2.84 g, 15.96 mmol) and 2,2-azobisisobutyronitrile (0.13 g, 0.798 mmol) in carbon tetrachloride (160 mL) was stirred under nitrogen atmosphere at 95° C. overnight. Then more N-bromosuccinimide (0.566 g, 3.18 mmol) and 2,2-azobisisobutyronitrile was added and the reaction was stirred under nitrogen atmosphere at 95° C. overnight. The reaction mixture was then washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column (9:1 hexane/ethyl acetate) to give tert-butyl N-[4-bromo-3-(bromomethyl)phenyl]-N-(4-cyanophenyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([O:17][S:18](=[O:25])(=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH3:26]N(C=O)C.C(=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([O:17][S:18](=[O:24])(=[O:25])[N:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH:14]=[N:15][CH:16]=3)[N:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CCOC(C)=O
Product: CCN(CC)S(=O)(=O)Oc1cncc(-c2cc3ccc(Cl)cc3n2C)c1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A flask is charged with diethyl-sulfamic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester (0.175 g, 0.560 mmol) and DMF (5 mL). Dimethyl carbonate (0.116 mL, 1.38 mmol) and potassium carbonate (0.035 g, 0.253 mmol) are added and the reaction is stirred at 150° C. overnight. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (heptane-ethyl acetate, 3:1) to afford diethyl-sulfamic acid 5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester as a yellow solid. MS (ESI) m/z 394.04 (M+H)+