Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C2C=CC=CC=2)C=CC([C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=CC=1>>[O:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Product: O=C(Cc1ccccc1)c1ccc(N2CCOCC2)cc1
Yield: 36 %

Procedure:
Prepared from 4-(4-bromophenyl)morpholine following the procedure described in Intermediate 14, where the crude product was purified by column chromatography (PE:EtOAc=5:1) to afford Intermediate 25 (280 mg, yield 36%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=O)[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[S:26])[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(N)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A solution of (R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1.31 g, 6 mmol) in dioxane (20 mL) was treated under argon with Lawesson's reagent (1.16 g, 3 mmol). The mixture was stirred at room temperature overnight. The volatiles were evaporated and the resulting white solid purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (0.74 g, 47%), MS (ISP): 245.4 (M+H)+..
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([OH:18])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[Na+]>C(Cl)Cl>[C:10]([F:7])(=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(O)c1ccccc1
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Yield: 80 %

Procedure:
Diethylaminosulfur trifluoride, 2.5 ml (0.02 mole) was slowly added to a stirred solution of 2.44 g (0.02 mole) of benzoic acid in 20 ml methylene chloride cooled to 0°. Powdered sodium fluoride, 1 g, was added to remove the HF, and the reaction mixture was filtered. The filtrate was distilled to give 1.98 g (80%) of benzoyl fluoride as a colorless liquid, bp 50° (10 mm) (identified by its infrared spectrum).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[NH2:14][CH2:15][CH2:16][SH:17].C1(C)C=CC=CC=1>O>[CH2:2]([CH:1]1[NH:14][CH2:15][CH2:16][S:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCS
Reactant: CCCCCCCCCCC=O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC1NCCS1

Procedure:
A mixture of 34 g. of undecylaldehyde and 22.8 g. of 2-aminoethanethiol hydrochloride in about 400 ml. of toluene was heated at reflux overnight. The water of condensation was collected in a Dean-Stark trap. The reaction mixture then was washed with aqueous sodium hydroxide and dried over anhydrous magnesium sulfate. After filtering the reaction mixture, the toluene was distilled under reduced pressure. The residue then was vacuum distilled, b.p. 130°-8°/0.1 mm, giving 2-decylthiazolidine. The following elemental microanalysis was obtained:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.ClCC(OC(=O)CCl)=O.[CH2:19]([N:21](CC)CC)[CH3:20].O>C1C=CC=CC=1>[NH2:21][CH2:19][CH2:20][NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CCN(CC)CC
Agent: O=C(CCl)OC(=O)CCl
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C)nc(NCCN)c1
Reaction time: 3 h

Procedure:
2-amino-4,6-dimethylpyridine(1.69 g), chloroacetic anhydride(3.54 g), and triethylamine(3.83 ml) were stirred in benzene(30 ml) for 1 hour while being cooled with ice. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. To the solution of the residue in dimethylformamide(23 ml) was added potassium phthalimide(2.82 g) and then the mixture was refluxed with stirring for 3 hours. After a large amount of water was added thereto, the depositing crystals were collected by filtration. The solution of the crystals in ethanol(50 ml), with hydrazine monohydrate(1.34 ml) added thereto, was refluxed with stirring for 3 hours and then concentrated under a vacuum. The residue, with water added thereto, was acidified with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then was concentrated under a vacuum. The solution of the residue in tetrahydrofuran(45 ml) was dropped into the suspension of lithium aluminium hydride(0.64 g) in tetrahydrofuran(45 ml) while being cooled with ice and the mixture was stirred at room temperature for 1 hour. A small amount of water was added thereto and then the resulting deposit was filtrated out. The filtrate was concentrated under a vacuum, thereby yielding 1.90 g of the aimed compound.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:13]=[CH:12][N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]=2[N:8]=[CH:9][CH:10]=1)=[NH:4].N1C=CC=CC=1.[C:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=O)#[N:29]>C(#N)C>[CH3:19][Si:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][O:15][CH2:14][N:11]1[C:7]2=[N:8][CH:9]=[CH:10][C:5]([C:3]3[N:4]=[C:33]([C:32]4[CH:31]=[C:30]([CH:38]=[CH:37][CH:36]=4)[C:28]#[N:29])[O:1][N:2]=3)=[C:6]2[CH:13]=[CH:12]1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(C(=N)NO)ccnc21
Solvent: CC#N
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3noc(-c4cccc(C#N)c4)n3)ccnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
The crude product N-hydroxy-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine-4-carboximidamide (0.06 gm, 0.0002 mol) was dissolved in pyridine (1.0 mL, 0.012 mol) and then 3-cyanobenzoyl chloride (0.040 g, 0.00024 mol) was added at rt. This mixture was stirred for 1 h and heated to 80° C. in an oil bath. After heating for 18 h the reaction was allowed to cool to rt and then diluted with ACN and concentrated in vacuo to give 3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazol-5-yl]benzonitrile 0.08 gm as an off white residue, LC/M S (M+H)+ 418.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13](COCC[Si](C)(C)C)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.CC1C=C(C#CC2N(COCC[Si](C)(C)C)C(C)=NC=2)C=CN=1>CCO.Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C#Cc2cn(COCC[Si](C)(C)C)c(C)n2)ccn1
Agent: Cc1cc(C#Cc2cnc(C)n2COCC[Si](C)(C)C)ccn1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-4-[2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-ylethynyl]-pyridine and 2-methyl-4-[2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-ylethynyl]-pyridine (2.85 g, 8.7 mmol) were dissolved in 50 mL EtOH saturated with HCl. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 50 mL water and adjusted to pH7 by addition of sodium hydroxide. The aqueous phase was extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (methylene chloride/methanol 100:5→85:15 gradient) and the desired compound was obtained as an off-white foam (1.19 g, 69%), MS: m/e=198.2 (M+H+). Method A2:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C@@H:33]1([CH2:43]O)[C@@H:42]2[N:37]([CH2:38][CH2:39][CH2:40][CH2:41]2)[CH2:36][CH2:35][CH2:34]1>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:43][C@H:33]4[C@@H:42]5[N:37]([CH2:38][CH2:39][CH2:40][CH2:41]5)[CH2:36][CH2:35][CH2:34]4)[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: OC[C@H]1CCCN2CCCC[C@H]12
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN2CCCC[C@H]12

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(1S,9aR)-octahydro-2H-quinolizin-1-yl methyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6) and [(1S,9aR)-octahydro-2H-quinolizin-1-yl]methanol following General Procedure J.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:5][C:4]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])#[N:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:35][O:36][CH:37]([O:41][CH3:42])[CH2:38][CH2:39]Br.C([O-])(O)=O.[Na+]>O1CCCC1.CCOC(C)=O>[C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])[CH2:39][CH2:38][CH:37]([O:41][CH3:42])[O:36][CH3:35])=[CH:5][C:4]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])#[N:2]
Reactant: Cc1nccn1Cc1ccc(C#N)c(Sc2ccc(Cl)cc2Cl)c1
Reactant: COC(CCBr)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(CCC(c1ccc(C#N)c(Sc2ccc(Cl)cc2Cl)c1)n1ccnc1C)OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Step D (317 mg, 0.850 mmol) in 2.0 mL of tetrahydrofuran at −78° C. was added lithium hexamethyldisilazide solution dropwise (1.02 mL, 1.02 mmol, 1.0 M in THF). After 45 minutes, 3-bromopropionaldehyde dimethyl acetal was added (0.231 mL, 1.70 mmol). The reaction was warmed to 0° C. and stirred for 2 hours, then poured into EtOAc/sat. NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (3-5% MeOH/CH2Cl2) to provide the desired product as a 1:1.5 mixture with the starting material.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:39])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:38][CH2:37]4)=[N:32]3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([O:8][CH2:7][C:6]([OH:40])=[O:5])=[C:10]2[C:15]=1[N:14]=[C:13]([O:20][CH:21]([F:22])[F:23])[C:12]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:37][CH2:38]4)=[N:32]3)=[CH:29][CH:30]=1)=[C:11]2[CH3:39]
Reactant: Cc1c(Cc2ccc(-n3ccc(C4CC4)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccc(-n3ccc(C4CC4)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
A solution of {8-chloro-3-[4-(3-cyclopropylpyrazol-1-yl)benzyl]-2-difluoromethoxy-4-methylquinolin-5-yloxy}acetic acid tert-butyl ester (0.11 g) in dichloromethane (8.0 mL) was treated with trifluoroacetic acid (2.0 mL), and the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium acetate solution and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulphate and then concentrated under reduced pressure to afford the title compound as a white solid (0.034 g).
Reaction SMILES: CN(C)C=O.[C:6]([OH:19])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(Cl)([Cl:22])=O>>[C:6]([Cl:22])(=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)Cl

Procedure:
82.2 g (1.13 mol) of N,N-dimethylformamide were added to 4.5 mol of lauric acid in a stirred apparatus. The reaction solution was brought to a temperature of from 40 to 50° C. with stirring, and a total of 5.06 mol of gaseous phosgene were introduced under atmospheric pressure. After the addition of phosgene was complete, the two phases were separated from one another. The catalyst phase comprised a molar proportion of the catalyst adduct, based on the molar amount of N,N-dimethylformamide plus catalyst adduct, of 0.50. The carbonyl chloride phase comprised 99.1 area % of lauroyl chloride and 0.15 area % of lauric acid. The color number was 268 APHA.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.Cl>CCOCC>[ClH:1].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nccn2n1
Reactant: NCc1ccccn1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(CNc2ccc3nccn3n2)nc1
Yield: 40 %

Procedure:
Prepared from 6-chloroimidazo[1,2-b]pyridazine (4) and 2-(aminomethyl)pyridine according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (135 mg, 40%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 8.68-8.67 (m, 1H), 8.27 (dt, J=1.5, 9.4 Hz, 1H), 8.03 (d, J=10 Hz, 1H), 7.99-7.98 (m, 1H), 7.90-7.87 (m, 2H), 7.72 (t, J=6.5 Hz, 1H), 7.40 (d, J=10 Hz, 1H), 4.80 (s, J=Hz, 2H); 13C NMR (75 MHz, CD3OD) δ 157.2, 156.8, 145.7, 144.4, 134.0, 125.9, 125.7, 122.3, 121.9, 121.4, 119.7, 45.5; HPLC tR=6.3 min (Luna), 98.9%; ES-MS: (M+H)=226 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[N:7]([CH3:18])[C:6]=2[CH:19]=1.[NH:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[C:21]([NH2:23])=[NH:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:22]=[C:21]([NH:20][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)[N:23]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[N:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: CN(C)C=C1CC(=O)N(C)c2cc(Cl)ccc2C1=O
Product: CN1C(=O)Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2ccc(Cl)cc21

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-1-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-m) and 4-guanidinobenzoic acid were converted to I-7 (30%): HRMS Calcd. for C20H15ClN4O3: 395.0910, Found 395.0923.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[CH:17]=[C:16]([CH2:18][C:19]4[CH:20]=N[CH:22]=[CH:23][CH:24]=4)[C:15](=[O:25])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][N:13]=4)[C:4]=2[CH:3]=1.[CH:26](=O)C1C=CC=CC=1>>[CH2:18]([C:16]1[C:15](=[O:25])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=4[N:8]3[CH:17]=1)[CH:11]=[CH:12][N:13]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:26][CH:20]=1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Cl)cc3c3ccnc1c32
Reactant: O=Cc1ccccc1
Product: O=c1c(Cc2ccccc2)cn2c3ccc(Cl)cc3c3ccnc1c32
Yield: 21.6 %

Procedure:
According to Example 1<step 4>, the compound (200 mg) produced in Example 23<step 4> was reacted with benzaldehyde (132 mg) to obtain the title compound (43 mg; 16%).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:21]([CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[CH:20][S:19][C:18]=3[CH:27]=2)[CH:8]=[CH:7][CH:6]=1.C1COCC1.Cl>O.C(OCC)(=O)C>[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:21]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][S:19][C:18]=3[CH:27]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CNc1cccc(CCOc2ccc3c(CCC(=O)[O-])csc3c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cccc(CCOc2ccc3c(CCC(=O)O)csc3c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
1N NaOH (10 ml) was added to a solution of 3-(6-{2-[6-(Methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)propanoate and THF (10 ml ). The reaction was stirred at room temperature for 16 h. The mixture was diluted with water and ethyl acetate. The separated aqueous layer was neutralized with 1 N HCl to pH=6.5. The resulting precipitate was filtered, washed with distilled water, and dried to yield 74 mg (55%) of 3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)propanoic acid as a white solid. NMR 1H DMSO-d6 δ: 7.67 (d, 1H, J=8.0 Hz), 7.58 (d, 1H, J=2.4 Hz), 7.31 (dd, 1H, J=7.2, 8.0 Hz), 7.18 (s, 1H), 7.00 (dd, 1H, J=2.4, 8.0 Hz), 6.45 (d, 1H, J=7.2 Hz), 6.37 (m, 1H), 6.27 (d, 1H, J=8.0 Hz), 4.36 (t, 2H, J=6.4 Hz), 2.99 (t, 2H, J=6.4 Hz), 2.90 (d, 3H, J=8.0 Hz), 2.64 (t, 2H, J=6.4 Hz). Mass Spectrum (LCMS, ESI) calculate for C19H21N2O3S 357.1 (M+H) found: 357.3.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([O:32]C)=[CH:30][CH:31]=2)=[CH:22][CH:21]=1)[CH3:19])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:34]>>[ClH:34].[NH2:8][C@@H:9]([C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][CH:27]=2)=[CH:22][CH:21]=1)[CH3:19])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11]
Reactant: COc1ccc(-c2ccc([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3CC[C@H](F)C3)cc2)cn1
Agent: Cl
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)[C@H](N)C(=O)N1CC[C@H](F)C1
Temperature: 100 °C

Procedure:
The product from Step A was dissolved in 3 mL of concentrated hydrochloric acid (37%). The reaction mixture was heated at 100° C. for 48 h before it was cooled to room temperature. The water was removed azeotropically with toluene. Purification by HPLC (YMC Pro-C18 column, gradient elution, 10–90% acetonitrile/water with 0.1% concentrated hydrochloric acid) afforded the title compound. LC/MS 344.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2([CH2:12]OS(C)(=O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:18]#[N:19].[Na+].O>CS(C)=O>[C:1]1([C:7]2([CH2:12][C:18]#[N:19])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccccc2)CCCC1
Reaction time: 16 h
Yield: 80 %

Procedure:
To a stirred solution of methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (279) (12 g, 47.24 mmol) in dimethyl sulfoxide (36 mL) were added KI (784 mg, 4.72 mmol) and NaCN (3.5 g, 70.87 mmol) and stirring was continued at 140° C. for 4 h and at room temperature for 16 h. After completion of the reaction, water (100 mL) was added. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic parts were washed with saturated ferrous sulfate solution (100 mL), water (3×10 0 mL) and brine (100 mL). After drying and concentrating the mixture, a crude product was obtained and purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to get (1-phenyl-cyclopentyl)-acetonitrile (280) (7 g, 79.98%) as a light yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N:12]1([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2cc(N3CCNCC3)ncc2c1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCN(c3cc4ccccc4cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.38 g of 4-methoxybenzoyl chloride are added dropwise to 10 g of 3-(piperazin-1-yl)-isoquinoline, dissolved in 40 ml of pyridine. After stirring for 1 hour at room temperature, the mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate phase is dried and the solvent is removed by evaporation. 5.8 g, melting point 156°-159° C., can be isolated.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].O>C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cccc(Oc2cccc(Cl)c2Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1cccc(Cl)c1Cl
Yield: 78.1 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(2,3-dichlorophenoxy)phenyl]acetate (3.7 g.), sodium hydroxide (880 mg.) and water (50 ml.) was treated in a similar manner to that of Example 5-(2). The resultant residue was pulverized with benzene, and the precipitates were collected by filtration and dried to give 2-[2-amino-3-(2,3-dichlorophenoxy)phenyl]acetic acid (2.65 g.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:22]1[C:23]2[N:24]([CH:29]=[CH:30][N:31]=2)[C:25]([Br:28])=[CH:26][N:27]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:10]([CH2:20][OH:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.C(OCC)(=O)C>[Br:28][C:25]1[N:24]2[CH:29]=[CH:30][N:31]=[C:23]2[C:22]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:32])[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[C:10]([CH:9]=2)[CH2:20][O:21][S:41]([CH3:40])(=[O:43])=[O:42])=[N:27][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)c(CO)c1)c1ncc(Br)n2ccnc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)c(COS(C)(=O)=O)c1)c1ncc(Br)n2ccnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.1 %

Procedure:
To a cooled solution (0° C.) of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(3-hydroxymethyl-4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.17 g, 0.34 mmol) in DCM (0.5 mL), is added triethylamine (0.104 mL, 0.74 mmol) followed by methanesulfonyl chloride (0.046 mL, 0.6 mmol). The reaction mixture is stirred at 0° C. for 1 hour and an additional hour at room temperature. The reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound (0.224 g) used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(F)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
Under ice cooling, to 5-fluoropyridine-2-amine (10.36 g) was added concentrated sulfuric acid (48 ml), followed by stirring for 10 minutes, and then fuming nitric acid (3.83 ml) was added dropwise over 30 minutes. Stirring was carried out at room temperature for 1 hour, and further at 55° C. for 90 minutes. Ice was poured thereinto, and neutralized with a 10 N aqueous sodium hydroxide solution, followed by concentration under reduced pressure. The residue was dissolved in dichloromethane (600 ml), followed by stirring for 30 minutes, and then the insolubles were filtered off to concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography to afford 5-fluoro-3-nitropyridine-2-amine (2.66 g).