Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:17]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[N:25][C:18]=3[N:19]([CH2:23][CH3:24])[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH:29]([C:26]1[CH:27]=[CH:28][C:17]2[C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=3)=[N:21][C:20](=[O:22])[N:19]([CH2:23][CH3:24])[C:18]=2[N:25]=1)[CH3:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)nc(=O)n(CC)c2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)Br)nc21
Temperature: 25 °C
Yield: 61.3 %

Procedure:
N-Bromosuccinimide (8.94 g, 50.2 mmol) and 200 mg of 2,2'-azobis(isobutyronitrile) were added to a solution of 15.0 g (47.8 mmol) of 4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one in 150 ml of carbon tetrachloride, followed by heating under reflux for 3 hours. The reaction solution was again mixed with 1.28 g (7.17 mmol) of N-bromosuccinimide and 100 mg of 2,2'-azobis(isobutyronitrile), followed by heating under reflux for 1 hour. After cooling to room temperature, insoluble matter was removed by filtration, and the resulting filtrate was mixed with water and extracted with carbon tetrachloride. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 11.5 g of 7-(1-bromoethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one in the form of crystals. The yield was 61%.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]C(O)=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].N1CCCCC1>O>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)c1ccc(C=O)cc1
Solvent: O
Solvent: C1CCNCC1
Product: CCN(CC)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 5.00 g (28 mmol) of 4-diethylaminobenzaldehyde, 5.62 g (31 mmol) of 4-nitrophenylacetic acid, 2.40 g (28 mmol) of piperidine, and 100 mL of xylenes was heated with stirring at reflux for 20 hours with continuous removal of water using a Dean-Stark apparatus. The mixture turned dark red. Approximately half the xylenes was distilled, and the residue was cooled to 3 0° C. Red crystals separated which were collected and then recrystallized from isopropanol/pyridine. Yield: 4.05 g (48%), mp 179-181 (lit2 182°-182.5° C.).
Reaction SMILES: C(=[C:4]([CH:6]([CH2:8][OH:9])[OH:7])[OH:5])(C)C.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:24]([O:9][CH2:8][CH:6]([OH:7])[CH2:4][OH:5])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CC(C)=C(O)C(O)CO
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOCC(O)CO
Temperature: 0 °C
Yield: 70 %

Procedure:
Isopropylideneglycerol (solketal, 26.4 g, 0.20 mol) in 60 mL of toluene was added dropwise to a solution of powered KOH (22.4 g, 0.04 mol) in 150 mL of toluene. The resulting mixture was refluxed for 4 h. 1-Bromododecane (50 g, 0.20 mol) in 40 mL of toluene was then added dropwise, and the solution was refluxed for 10 h. After cooling, the reaction mixture was diluted with 200 mL of ice-water and extracted with diethyl ether (3×100 mL). The ether layers were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in 60 mL of diethyl ether and 260 mL of MeOH. Concentrated HCl (60 mL) was added, and the solution refluxed for 16 h. After cooling, ice-water (150 mL) was addecl, and the layers separated. The aqueous layer was extracted with diethyl ether (2×75 mL). The combined organic fractions were then dried over sodium sulfate, filtered, and concentrated in vacuo. The solid residue was recrystallized from MeOH to give 37 g (0.14 mol, 71%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=O.Cl.[NH2:15][OH:16].[OH-].[K+]>CO.O>[Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[N:15][OH:16]
Reactant: NO
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(Cl)c(C=NO)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of Step 1 intermediate (56 g, 262.37 mmol) and hydroxylamine hydrochloride (22.8 g, 327.97 mmol) in methanol (525 ml) was added drop-wise a solution of KOH (18.3 g, 327.97 mmol) in water (32 ml) over a period of 1 h, while reaction mixture was maintained below 10° C. The mixture was stirred at room temperature for 1 h, and the resulting oxime precipitate was collected by filtration, washed with water (2×250 ml), methanol (2×150 ml) and dried to give 46.3 g of the product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 3.19 (s, 3H), 3.51 (s, 3H), 7.94 (s, 1H), 11.40 (br s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[CH:15][C:14]([CH:17]([OH:21])[CH2:18][CH2:19][CH3:20])=[C:13]([O:22][CH2:23][CH3:24])[CH:12]=1)[CH3:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[CH:32][CH:33]=1)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]([O:22][CH2:23][CH3:24])[C:14]([CH:17]([O:21][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([O:27][CH2:25][CH3:26])[CH:33]=2)[CH2:18][CH2:19][CH3:20])=[CH:15][N:16]=1)[CH3:2]
Reactant: CCCC(O)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reactant: CCOc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(Oc1cccc(OCC)c1)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butan-1-ol (67 mg, 0.20 mmol), 3-ethoxy-phenol (34 mg, 0.25 mmol), triphenylphosphine (65 mg, 0.25 mmol), and DEAD (36 mg, 0.25 mmol) in THF (1 mL) is stirred at room temperature overnight. Aqueous NH4Cl solution (5 mL) and hexane (10 mL) are added to the mixture, and the organic layer is separated. The organic layer is washed with NaHCO3 solution, brine, dried over Na2SO4, and concentrated. The residue is purified by PTLC to give 2-(2,6-diethyl-phenyl)-5-[1-(3-ethoxy-phenoxy)-butyl]4-ethoxy-pyridine. 1H NMR (CDCl3) 8.55 (s, 1H), 7.27 (m, 1H), 7.07-7.14 (m, 3H), 6.73 (s, 1H), 6.43-6.49 (m, 3H), 5.57 (m, 1H), 4.13 (q, 2H), 3.95 (q, 2H), 2.56-2.37 (m, 4H), 1.85-2.05 (m, 2H), 1.40-1.60 (m, 5H), 1.37 (t, 3H), 0.96-1.08 (m, 9H).
Reaction SMILES: O1CCCCC1[O:7][C:8]1(/[CH:14]=[CH:15]/[CH2:16][N:17]2[C:21](=[O:22])[CH2:20][S:19][CH:18]2[CH2:23][CH2:24][CH2:25][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[OH:7][C:8]1(/[CH:14]=[CH:15]/[CH2:16][N:17]2[C:21](=[O:22])[CH2:20][S:19][CH:18]2[CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:35][CH:36]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccc(CCCC2SCC(=O)N2C/C=C/C2(OC3CCCCO3)CCCCC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2C/C=C/C2(O)CCCCC2)cc1
Reaction time: 20 h

Procedure:
A solution of the ester product of Step B above (4.5 g., 8.7 mmole) and pyridinium tosylate (220 mg., 0.87 mmole) in ethanol (50 ml.) is let stand at 25° C. for 2.5 hours. To this reaction solution is added a solution of sodium hydroxide (1.2 g., 30 mmole) in water (12 ml.). The resulting soluton is let stand at 25° C. for 20 hours. The ethanol is then evaporated at reduced pressure. The residue is dissolved in water, and the solution acidified with 2 N hydrochloric acid to precipitate the product as a yellow gum. It is chromatographed on 60 g. of silica gel with elution by 2% methanol in chloroform. The purified title product is obtained as a yellowish, viscous oil weighing 2.4 g.; pmr (CDCl3) δ2.74 (2H, brt, CH2Ph), 3.55 (2H, brs, COCH2S), 4.70 (1H, brd, SCHN), 5.70 (2H, m, CH=CH), 6.53 (2H, brs, OH and CO2H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](O)(=O)[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[SH:8].CO>ClC1C=CC=CC=1Cl>[NH:3]1[CH2:2][CH2:1][N:4]=[C:5]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[SH:8]
Reactant: NCCN
Reactant: O=C(O)c1ccccc1S
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: Sc1ccccc1C1=NCCN1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
21.6 mL (0.323 mol) of ethylenediamine was added to a suspension of 20.0 g (0.112 mol) of thiosalicylic acid in 200 mL of 1,2-dichlorobenzene, and refluxed under nitrogen for 4 h then cooled to ca. 60° C. and 50 mL of methanol was added. The solution was allowed to stand at 22° C. overnight and the resulting yellow crystalline solid was collected and washed with ether to give 10.6 g of pure product.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.OC(COCC=C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[C:24]([Cl:1])[CH:25]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: C=CCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)c(Cl)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M−15,0.1), 279 (10), 279 (9), 278 (63), 276 (100), 163 (9), 146 (5), 121 (29).
Reaction SMILES: [C:1](=[S:4])([NH2:3])[CH3:2].Cl[CH:6]([C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>CCO>[CH3:2][C:1]1[S:4][C:6]([C:7]([OH:9])=[O:8])=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Reactant: CC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)c(C(=O)O)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of ethanethioamide (80.0 g, 1.06 mol) in EtOH (600 mL), was added ethyl 2-chloro-3-oxo-3-phenylpropanoate (141.5 g, 0.64 mol), which was prepared by published procedure in M. Altuna-Urquijo, et al.; Tetrahedron; 65; 2009; 975-984, and the mixture was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to 50° C., 8N aqueous sodium hydroxide solution (120 mL) was added, and the mixture was stirred 80° C. for 2 h. The reaction mixture was allowed to cool to 50° C., 8N aqueous sodium hydroxide solution (240 mL) was added, and the mixture was stirred 80° C. for 1 h. The reaction mixture was allowed to cool to 0° C., and was then neutralized by the addition of 6N hydrochloric acid (400 mL). The mixture was stirred at rt for 12 h and the resulting precipitate was collected by filtration and washed with water, EtOH and diethyl ether sequentially to give the title compound (105.6 g, 75%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C@H:10]1[CH2:9][C@@H:8]([NH2:7])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of tert-butyl(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)carbamate (0.40 g, 1.252 mmol) in Dioxane (5 mL) was treated with hydrogen chloride, 4N in 1,4-dioxane (6.26 ml, 25.05 mmol). The resulting solution was stirred at room temperature for 2 h and concentrated to give the desired product cis —N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine dihydrochloride (0.301 g, 1.030 mmol, 82% yield). 117243-44-1. The product was used in next step without further purification. m/z: 220.1 (M+1) (−2HCl)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:35](=[O:37])[CH:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nc2ccccc2o1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nc2ccccc2o1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
A solution of triphenylphosphine (274 mg, 1.04 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (211 mg, 1.18 mmol). The resulting brownish-purple mixture was stirred at 0° C. for 5 min until the reaction mixture became homogeneous. The reaction mixture was then treated with 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 1, 200 mg, 0.70 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzoxazole (140 mg, 1.04 mmol) and pyridine (0.17 mL, 2.09 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 80/20 hexanes/ethyl acetate) afforded N-benzoxazol-2-yl-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (214 mg, 76%) as a light yellow foam: EI-HRMS m/e calcd for C21H20Cl2N2O2 (M+) 402.0902, found 402.0908.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.F[C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[C:10]2=[N:11][CH:12]=1.[NH3:38].[Cl-].[Na+]>C(#N)C>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:13]1[C:10]2=[N:11][CH:12]=[CH:7][CH:8]=[C:9]2[C:15]([C:16]2[N:17]=[N:18][C:19]3[C:23]([CH3:28])([CH3:29])[C:24](=[O:26])[NH:38][C:20]=3[N:21]=2)=[N:14]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1O
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 ml of phosphoryl chloride were added to 9.700 g (22.025 mmol) of the compound from Example 61A, and the mixture was stirred at RT overnight. The reaction mixture was dissolved in 150 ml of acetonitrile and, with ice cooling, stirred into a mixture of 1337 ml of concentrated aqueous ammonia solution (35% strength) and 1300 ml of acetonitrile. The mixture was stirred at room temperature for 2 days. 300 g of sodium chloride were then added. Two phases formed. The organic phase was separated off and concentrated to dryness. The residue was taken up in ethyl acetate (150 ml). A precipitate formed and was filtered off with suction through a frit. The filter cake was washed three times with water and then three times with ethyl acetate (5 ml). The residue was dried under high vacuum. This gave 4.58 g (51% of theory) of the title compound.
Reaction SMILES: [CH2:1]1[C@@H:4]([C:5]([OH:7])=[O:6])[NH:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[C:19]([Cl:21])[CH:20]=1>O.CCOCC>[Cl:21][C:19]1[CH:18]=[C:17]([S:22]([N:3]2[CH2:2][CH2:1][CH:4]2[C:5]([OH:7])=[O:6])(=[O:23])=[O:24])[CH:16]=[C:15]([Cl:14])[CH:20]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)[C@@H]1CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)C1CCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 2.0 g (19.8 mmol) of (L)-azetidine-2-carboxylic acid and 4.6 g (43.6 mmol) of Na2CO3 in 100 mL of H2O at 0° C. was added 5.8 g (23.8 mmol) of 3,5-dichlorophenylsulfonylchloride. The reaction was allowed to come to room temperature overnight and was then diluted with Et2O and H2O. The layers were separated and the organic phase was discarded. The aqueous phase was acidified to pH˜4 with 1M HCl and extracted with EtOAc (4×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give N-(3,5-dichlorophenylsulfonyl)-azetidine-2-carboxylic acid (6.0 g, 100%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][C:8]=1[Cl:17])C.[Br:19]Br>CO.Cl>[Cl:17][C:8]1[CH:9]=[C:10]([C:13](=[O:16])[CH:14]([Br:19])[CH3:15])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([O:3][CH3:1])=[O:18]
Reactant: BrBr
Reactant: CCOC(=O)COc1ccc(C(=O)CC)cc1Cl
Agent: Cl
Solvent: CO
Product: COC(=O)COc1ccc(C(=O)C(C)Br)cc1Cl

Procedure:
Ethyl-2-(2-chloro-4-propionylphenoxy)acetate (4 g) was dissolved in methanol (40-50 ml). HCl (2 drops, conc) was added, followed by the dropwise addition over 5-10 minutes of bromine (2.62 g, 0.016 mole). After the bromine addition was complete the mixture was heated on a steam bath for 15-30 minutes allowing much of the solvent to evaporate. The residue was washed with cold water and the remaining solid recrystallized several times from hexane to give methyl 2-[2-chloro-4-(2-bromopropionyl)phenoxy]acetate (4.6 g, 90%, mp 63°-65° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:33])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:6])=[O:4].[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C>[C:34]([NH:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:33])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)[CH3:6])=[O:4])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)CN)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(=O)NCC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and acetic anhydride in glacial acetic acid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[N:9]([CH2:21][C:22](O)=[O:23])[N:8]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH:27]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[N:9]([CH2:21][C:22]([NH:25][CH2:26][CH:27]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1C(F)(F)F
Product: CC(C)(C)OC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F

Procedure:
Analogously to the procedure of Example 63, 54 mg (146 μmol) of [3-(5-chloro-2-thienyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 154A in WO 2007/134862] were reacted with 49 mg (161 μmol) of tert-butyl {2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate. This gave 64 mg (67% of theory) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8].C(O)(=O)C(O)=O.[CH3:18][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][SH:28])=[CH:24][CH:23]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[CH3:20][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][S:28][CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8])=[CH:24][CH:23]=1)[CH3:18]
Reactant: CN(C)Cc1ccc(CS)o1
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 120 h
Yield: 63.9 %

Procedure:
A mixture of N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (0.9 g), 5-[(dimethylamino)methyl]-2-furanmethanethiol oxalate (1:1) (1.3 g) and potassium carbonate (2.7 g) in water (10 ml) and tetrahydrofuran (10 ml) was stirred under nitrogen at room temperature for 5 days. The suspension was evaporated in vacuo, the residue mixed with water (40 ml) and the suspension extracted with ether (2×30 ml). The aqueous fraction was evaporated in vacuo and the residue evaporated with ethanol (2×10 ml). Tetrahydrofuran (20 ml), MgSO4 and decolourising charcoal were added and after 1 hour the mixture was filtered. Evaporation of the filtrate gave an oil (1 g) which was chromatographed (silica/methanol: 0.88 ammonia, 79:1). The appropriate eluate was evaporated and the oily residue (0.66 g) extracted with hot isopropyl acetate. The solid which separated was filtered to give the title compound (0.4 g), m.p. 65°-68°, which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent No. 1,565,966.
Reaction SMILES: Cl[C:2]([C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][C:4]#[N:5].Cl.[CH2:14]([CH:16]1[CH2:18][CH:17]1[NH2:19])[CH3:15].C(N(CC)CC)C>C(#N)C>[Cl:12][C:7]1[C:6]([C:2]([NH:19][CH:17]2[CH2:18][CH:16]2[CH2:14][CH3:15])=[CH:3][C:4]#[N:5])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CCC1CC1N
Reactant: N#CC=C(Cl)c1cccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC1CC1NC(=CC#N)c1cccnc1Cl
Yield: 57.3 %

Procedure:
To a solution of 3-chloro-3-(2-chloropyridin-3-yl)acrylonitrile (1.4 g, 7.03 mmol, 1 eq.) in 15 ml of acetonitrile was added 2-ethylcyclopropanamine hydrochloride (1.02 g, 8.44 mmol, 1.2 eq.) followed by triethylamine (TEA) (1.06 g, 10.55 mmol, 1.5 eq.). The reaction was microwaved (130° C., 2000 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was triturated in ethyl acetate and the white solid removed by filtration. After concentration under vacuum, the residual oil was subjected to column chromatography to give 3-(2-chloropyridin-3-yl)-3-[(2-ethylcyclopropyl)amino]acrylonitrile (0.998 g, 51% yield).