Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.[O-]CC.[Na+].Br[CH2:20]/[CH:21]=[CH:22]/[CH2:23]Br.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:22]1[CH:21]=[CH2:20])=[O:8])[CH3:11]
Reactant: BrC/C=C/CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.6 %

Procedure:
35.4 g (221 mmol) of diethyl malonate and 402 mL of toluene were added into a three-necked flask (1 L), and thereafter, 82.7 mL (211 mmol) of a 20% sodium ethoxide ethanol solution was added thereto as a base. The obtained mixture was stirred at room temperature for 0.5 hours, and 21.5 g of trans-1,4-dibromo-2-butene (101 mmol; a reagent manufactured by Sigma-Aldrich) was then added to the reaction solution. The obtained mixture was stirred at room temperature for 22 hours, and 241 mL of a 1 M sodium hydroxide aqueous solution was then added to the reaction solution. The mixture was stirred for 1 hour, and an organic layer was then separated. A water layer was re-extracted with 240 mL of toluene, and organic layers were then gathered. The gathered organic layer was washed with 240 mL of water three times. The resultant was filtrated, while washing the residue with toluene. The obtained filtrate was concentrated at 45° C. under reduced pressure, so as to obtain 23.6 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane in the form of a crude product of a light yellow oily substance. This crude product contained 21.2 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane (yield: 99%).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[F:18][C:19]([F:34])([F:33])[C:20]([N:22]1[C:27]2[CH:28]=[C:29](I)[CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1)=[O:21]>>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]4[O:25][CH2:24][CH2:23][N:22]([C:20](=[O:21])[C:19]([F:33])([F:18])[F:34])[C:27]=4[CH:28]=3)([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: O=C(N1CCOc2ccc(I)cc21)C(F)(F)F
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc3c(c1)N(C(=O)C(F)(F)F)CCO3)O2

Procedure:
This compound was prepared by coupling rac-3,4-dihydro2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol (1.15 g or 5 mmol) with 4-(trifluoroacetyl)-3,4-dihydro-6-iodo-2H-1,4-benzoxazine (1.95 g or 5.5 mmol) under the conditions described in Example 15. The product was isolated by chromatography over the 40 fold amount of silica gel methylene chloride. It was crystallized from ether/hexane and recrystallized twice from methanol to give colorless crystals with m.p. 153°-155°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH2:11])[CH2:5]2.C(N(C(C)C)CC)(C)C.Cl[CH2:22][CH2:23][C:24]1[CH:32]=[C:31]([O:33][CH2:34][C@@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([N:11]1[CH2:22][CH2:23][C:24]3[C:25](=[CH:29][CH:30]=[C:31]([O:33][CH2:34][C@@H:35]4[CH2:39][CH2:38][CH2:37][O:36]4)[CH:32]=3)[C:26]1=[O:27])[CH2:5]2
Reactant: O=C(Cl)c1ccc(OC[C@@H]2CCCO2)cc1CCCl
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@@H]1Cc2ccc(Br)cc2C1
Reaction time: 0.08 h

Procedure:
A mixture of (R)-5-bromoindan-2-ylamine (hydrochloride, 1.05 g), THF (20 ml) and diisopropylethylamine (1.0 g) was admixed with 2-(2-chloroethyl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzoyl chloride (1.28 g; from 6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-isochroman-1-one by boiling with thionyl chloride). After 5 minutes, potassium tert-butoxide (1.42 g) was added. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:1 ethyl acetate/heptane). This afforded the product with the molecular weight of 442.36 (C23H24BrNO3); MS (ESI): 442 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)[CH3:9].C(OC(=O)[NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:41]=[C:40]([CH:42]=O)[NH:39][N:38]=2)=[CH:33][CH:32]=1)(C)(C)C>CN(C=O)C>[CH2:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:21]=[CH:20][C:19]3[NH:22][C:42]([C:40]4[NH:39][N:38]=[C:37]([C:34]5[CH:35]=[CH:36][C:31]([NH2:30])=[CH:32][CH:33]=5)[CH:41]=4)=[N:23][C:18]=3[CH:17]=2)[CH2:14][CH2:15]1)[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(C=O)[nH]n2)cc1
Reactant: CCN1CCN(c2ccc(N)c(N)c2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCN(c2ccc3[nH]c(-c4cc(-c5ccc(N)cc5)n[nH]4)nc3c2)CC1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Triethylamine (509 μL, 3.62 mmol) was added to a solution of 4-(4-ethylpiperazin-1-yl)-benzene-1,2-diamine as the tetra-hydrochloride salt in anhydrous DMF (4 mL). After five minutes, a solution of [4-(5-formyl-1H-pyrazol-3-yl)phenyl]carbamic acid tert-butyl ester in anhydrous DMF (2 mL) was added to the diamine. The reaction flask was left open to the air and heated to 65° C. After twelve hours the reaction was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the product (87 mg, 99% yield) as a light purple solid. Note that the BOC group was removed under the purification conditions: 1H NMR (400 MHz, CDCl3): δ 7.90 (m, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.46 (m, 2H), 7.42 (dd, J=9.2, 2.0 Hz, 1H), 7.41 (s, 1H), 7.30 (d, J=2.4 Hz, 1H), 4.01 (bd, J=12.0 Hz, 2H), 3.74 (bd, J=10.4 Hz, 2H), 3.35-3.27 (m, 4H), 3.23 (m, 2H), 1.44 (t, J=7.2 Hz, 3H); MS (EI) for C22H25N7: 388.2 (MH+).
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.Br[C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][CH:27]=1>>[NH:32]1[C:33]2[C:29](=[CH:28][CH:27]=[C:26]([C:12]#[C:11][C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:34]=2)[CH:30]=[CH:31]1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Brc1ccc2cc[nH]c2c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc3cc[nH]c3c2)c1)c1ccccc1
Yield: 17.9 %

Procedure:
In a manner similar to that described in Example 443, (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 6-bromoindole (90.7 mg, 0.46 mmol) were reacted to give the title compound (30 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][OH:17])=[CH:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>O>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([O:17][CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=[CH:9][C:10]4=[N:15][CH:14]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: OCc1cnc2ccc(-c3ccccc3)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(OCc3cnc4ccc(-c5ccccc5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
In a microwave vessel, (6-phenylimidazo[1,2-b]pyridazin-3-yl)methanol (0.075 g, 0.33 mmol), 4-chloro-7-methoxyquinoline (0.19 g, 1.00 mmol), Cs2CO3 (0.22 g, 0.67 mmol) and 0.7 mL DMSO were combined and the vessel sealed. The mixture was pre-stirred for 2 min, followed by microwave heating for 2 h at 120 C, then 1 h at 130 C. The mixture was allowed to cool to rt, diluted with water to precipitate a cream solid. The solid was collected and rinsed with water. The solid was purified via flash chromatography using a 0% to 5% MeOH in EtOAc gradient to afford the title compound as a yellow solid. M/Z=383.2 [M+H], calc 382.4212 for C23H15N4O2.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][CH:16]=[N:15][CH:14]=2)=[CH:9][CH:8]=1.CN([CH:21]=[O:22])C.Cl>C1COCC1.CCOCC>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][C:16]([CH:21]=[O:22])=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2cnco2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ncc(-c2ccc(F)cc2)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A solution of nBuLi (1.6 M in hexane, 3.45 ml, 5.53 mmol) was added dropwise at −78° C. to a stirred solution of 5-(4-fluorophenyl)-1,3-oxazole (0.82 g, 5.03 mmol) in THF (10 ml) (Organic Letters (2001),(3)2, 271-273). The mixture was stirred at −78° C. for 30 minutes and then quenched with DMF (0.43 ml, 5.53 mmol). It was gradually warmed to room temperature, stirred for further 30 minutes, diluted with Et2O (30 ml), then neutralised with 1N HCl. The organic layer was separated, washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel eluting with DCM afforded 5-(4-fluorophenyl)-1,3-oxazole-2-carbaldehyde (0.58 g, 60%): δH (360 MHz, CDCl3) 7.18 (2H, t, J 8.6 ), 7.58 (1H, s), 7.77-7.81 (2H, m), 9.76 (1H, s); m/z (ES+) 192 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CSCc1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of ethyl 2-(4-fluorobenzylthio)acetate (1.89 g, 8.29 mmol) in DCM (20.0 mL) at −40° C. was added a solution of m-CPBA (77%, 1.86 g, 8.29 mmol) in DCM (20.0 mL) dropwise. The solution was stirred from −40° C. to room temperature overnight. The solution was then quenched with polymer bound diethylene triamine. After filtration and concentration, the residue was purified by flash chromatography on SiO2 to give ethyl 2-(4-fluorobenzylsulfinyl)acetate (2.0 g, 98% yield). MS (ESI+): m/z 267.09 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:6]=2[CH:27]=1.[CH2:28]([N:30]([CH2:39][CH3:40])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([CH3:38])[CH:32]=1)[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:30]([CH2:39][CH3:40])[CH2:28][CH3:29])=[CH:32][C:33]=3[CH3:38])=[S:16])[N:8]=[C:7]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:6]=2[CH:27]=1
Reactant: COc1ncc(C2=NC(N=C=S)C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Reactant: CCN(CC)c1ccc(N)c(C)c1
Product: CCN(CC)c1ccc(NC(=S)NC2N=C(c3cnc(OC)nc3OC)c3cc(Cl)ccc3N(C)C2=O)c(C)c1
Temperature: 70 °C
Yield: 87.1 %

Procedure:
As illustrated in the scheme above, a solution of 7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1,3-dihydro-3-isothiocyanato-1-methyl-2H-1,4-benzodiazepin-2-one (0.069 g, 0.146 mmol) and N4,N4-diethyl-2-methyl-1,4benzenediamine (0.029 g, 0.161 mmol) in (CH2Cl)2 (5.0 mL) was heated at 70° C. for 16 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (7:3 CH2Cl2:EtOAc) to provide the title compound as a light orange solid (0.074 g, 87%). 1H-NMR (CDCl3): δ 8.64 (s, 1H), 7.52 (dd, J=2.5 Hz, J=8.8 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.17-7.13 (m, 1H), 6.54-6.51 (m, 2H), 6.06 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.74 (s, 3H), 3.42 (s, 3H), 3.40-3.27 (m, 4H), 2.30 (s, 3H), 1.17 (t, J=7.1 Hz, 6H). HRMS calculated for (C28H32ClN7O3S+H) (M+H)+: 582.2054. Found (ESI): 582.2076.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH3:23])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
Methyl 2-(3,4-dichlorophenylsulfonamido)benzoate (21.3 g, 59.1 mmol) was dissolved in acetone (300 ml), and K2CO3 (16.3 g, 118.3 mmol, 2 eq.) was added thereto. Methyl iodide (7.4 ml, 118.3 mmol, 2 eq.) was then added, and the suspension was heated overnight at 40° C. The solid materials were filtered off and the filtrate was concentrated using a rotary evaporator. Purification was carried out by filtration over silica gel (DCM).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Br:24])[C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(C)cccc1OCCCC(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: Clc1ccccc1
Product: CCOC(=O)/C=C/c1c(CBr)cccc1OCCCC(=O)OCC
Temperature: 85 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 4-[2-((E)-2-ethoxycarbonyl-vinyl)-3-methyl-phenoxy]-butyric acid ethyl ester (8.0 g, 25.0 mmol) in chlorobenzene (190 mL) were added N-bromosuccinimide (6.67 g, 37.5 mmol) and 2,2′-azobisisobutyronitrile (AIBN) (591 mg, 3.6 mmol) at room temperature. Then, the solution was heated to 85° C. and stirred for 1 h. Then, the reaction mixture was cooled to room temperature and diluted with water (100 mL). Then, the organic compound was extracted into hexanes (3×100 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a crude oil. The crude oil was purified by using a Biotage (40 L) column eluting with 15-25% ethyl acetate in hexanes to isolate 4-[3-bromomethyl-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (7.11 g, 71%) as a low melting solid: ES(+)-HRMS m/e calculated for C18H23BrO5 (M+Na)+ 421.0621, found 421.0621.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])#[N:2].[CH3:15][C:16]1([CH3:27])[O:21][C:20](=[O:22])[C:19](=[CH:23]OC)[C:18](=[O:26])[O:17]1>C(O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:23]=[C:19]2[C:18](=[O:26])[O:17][C:16]([CH3:15])([CH3:27])[O:21][C:20]2=[O:22])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])#[N:2]
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: COCCOc1cc(N)ccc1C#N
Solvent: CCO
Product: COCCOc1cc(NC=C2C(=O)OC(C)(C)OC2=O)ccc1C#N
Yield: 60.6 %

Procedure:
4-Cyano-3-(2-methoxyethoxy)aniline (760 mg, 4 mmol) and 2,2-dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (1.0 g, 5.4 mmol), (Montatsh. Chem. 1967, 98, 564), in ethanol (20 ml) was heated at reflux for 1 hour. The mixture was allowed to cool and the solid collected by filtration to give 5-((4-cyano-3-(2-methoxyethoxy)anilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (840 mg, 61%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3nsc(-c4cnc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2cnc(OC(C)C)c(Cl)c2)n1
Yield: 49.1 %

Procedure:
To a solution of ethyl 1-{2-[3-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D112) (200 mg, 0.368 mmol) in Isopropanol (8 mL) and Water (8.00 mL) was added NaOH (3.68 mL, 1.841 mmol). The reaction was stirred at 90° C. for 2 hr before the isopropanol was removed in vacuo. The residue was acidified with aq HCl (2 M) until pH ˜2. The aqueous layer was extracted with ethyl acetate and the organic phases were dried and concentrated, purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylic acid (E75) (93 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.06 (3H, t), 1.28 (6H, d), 1.68 (2H, m), 2.05 (2H, m), 2.51 (1H, m), 2.73 (2H, m), 3.07 (4H, m), 3.23 (2H, m), 3.48 (1H, m), 3.64 (1H, m), 5.37 (1H, m), 7.30 (2H, m), 7.68 (1H, d), 8.47 (1H, d), 8.81 (1H, d), 9.54 (1H, s br). δF (DMSO-d6, 376 MHz): −73.6. MS (ES): C26H31ClN4O3S requires 514.2. found 515.0 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12](Cl)=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:24].[Na]>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([SH:24])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S
Reactant: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1Cl
Agent: [Na]
Product: O=C(NCc1ccccc1)c1cnc(-c2ccccc2)nc1S
Yield: 16.2 %

Procedure:
Using the procedure from Preparation 34, 5.8 g (17.9 mol) of 4-chloro-2-phenyl-pyrimidine-5-carboxylic acid benzylamide was reacted with 5.1 g (72 mmol) of sodium hydrogen sulfide to give 3.75 g of the title compound, mp 189°-193° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:9][CH:8]=2)[O:4][N:3]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:24]/[CH:25]=[CH:26]/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:11][CH:12]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(CC(=O)c3ccccc3)cc2)n1
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(C(C/C=C/c3ccccc3)C(=O)c3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-1-phenyl 1-ethanone (0.2 g, 0.72 mmole) in DMF (3 mL) was added NaH (0.022 g, 0.7 mmole) at 0° C. The reaction was stirred for 15 min. Then a solution of cinnamyl bromide (0.16 g, 0.84 mmol) in 1 mL DMF was added. The reaction was warmed to room temperature, and was then quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was then dried (Na2SO4), filtered, and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:12]1([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([NH2:28])[C:25]([NH2:27])=[O:26])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.CCN(C(C)C)C(C)C>CS(C)=O>[N:12]1([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C@@H:24]([NH:28][C:8]3[CH:9]=[C:2]([Br:1])[C:3]([C:4]#[N:5])=[CH:6][C:7]=3[F:11])[C:25]([NH2:27])=[O:26])=[CH:21][CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: N#Cc1cc(F)c(F)cc1Br
Reactant: NC(=O)[C@H](N)Cc1ccc(-n2ccnc2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(F)c(N[C@H](Cc2ccc(-n3ccnc3)cc2)C(N)=O)cc1Br
Yield: 31.7 %

Procedure:
A solution of 2-bromo-4,5-difluorobenzonitrile (100 mg, 0.458 mmol), ((R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-aminopropanamide (100 mg, 0.434 mmol) and DIEA (0.100 mL, 0.575 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. The mixture was purified by HPLC to give (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(5-bromo-4-cyano-2-fluorophenylamino)propanamide (59 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:37]2[C:38]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3Cl)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH2:21])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=[S:23].[NH4+].[OH-].O>C1COCC1>[CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH:21][C:22]([NH2:24])=[S:23])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Reaction time: 22 h
Yield: 70 %

Procedure:
3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-ylamine (0.97 mmol) is dissolved in THF (10 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 22 hours. 32% NH4OH (20 eq.) is added and stirred 2 hours at room temperature. Water (250 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. (3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiourea is obtained as yellow solid in a yield of 70%. HPLC (method C): 2.24 min; LC-MS (method A): 2.372 min, 344.15 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[S:33]1(=[O:39])(=[O:38])[CH2:37][CH2:36][CH2:35][NH:34]1>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:5]4[CH:4]=[CH:3][C:2]([N:34]5[CH2:35][CH2:36][CH2:37][S:33]5(=[O:39])=[O:38])=[CH:7][C:6]=4[N:8]4[CH2:12][CH2:11][N:10]([CH3:13])[C:9]4=[O:14])=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=2)[CH2:32][CH2:31]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2N2CCN(C)C2=O)CC1
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCN(C)C2=O)CC1
Yield: 38.4 %

Procedure:
Using 1-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (79 mg) described in Preparation Example 242 and isothiazolidine 1,1-dioxide (32 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (36 mg) was obtained.