Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH2:11][CH3:12])[CH2:9][NH:8][C:7](=S)[C:6]1=[O:14].[N:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[C:29]([NH:31][NH2:32])=O>C(O)CCC>[Cl:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH2:11][CH3:12])[CH2:9][N:8]2[C:29]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][N:23]=3)=[N:31][N:32]=[C:7]2[C:6]1=[O:14]
Reactant: NNC(=O)c1cnccn1
Reactant: CC[C@H]1CNC(=S)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Solvent: CCCCO
Product: CC[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A solution of Intermediate 6 (100 mg, 0.29 mmol) and pyrazine-2-carbohydrazide (39 mg, 0.29 mmol) in 1-butanol (3 mL) was heated to 130° C. for 16 h. After cooling to rt, the reaction was concentrated to give a brown oil. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a white solid (94 mg, 75%). MS (ESI): mass calcd. for C19H16ClF3N6O, 436.1; m/z found, 437.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.62 (d, J=1.5 Hz, 1H), 8.69 (d, J=2.5 Hz, 1H), 8.62 (dd, J=2.5, 1.6 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.69 (dd, J=7.8, 1.1 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 5.56-5.42 (m, 2H), 4.54 (d, J=15.5 Hz, 1H), 4.46 (dd, J=14.1, 4.4 Hz, 1H), 3.77 (ddd, J=9.4, 4.6, 3.5 Hz, 1H), 1.87-1.78 (m, 1H), 1.63-1.53 (m, 1H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4](OCC(N)=O)=[N:5][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].C[N:26](C)C=O>O.C(OCC)(=O)C>[NH2:26][C:4]1[N:5]=[C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(-c2ccco2)nc1OCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2ccco2)nc1N
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A suspension of 2-[[3-cyano-6-(2-furyl)-2-pyridyl]oxy]acetamide (8.0 g, 32.9 mmol) and potassium carbonate (9.1 g, 65.9 mmol) in N,N-dimethylformamide (80 ml) was stirred at 120° C. for 1.5 hours. After cooling as it was, the reaction solution was diluted with water and ethyl acetate, and the insoluble matters were filtered off. The aqueous layer in the filtrate was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated solution of ammonium chloride (×2), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in methanol, and the resulting solid was collected by filtration and washed with methanol, to give the title compound (3.81 g, 63%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:14][CH2:13]1)[C:7](=[C:15]=[O:16])[CH2:6][C:5]2=[O:17].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:13][CH2:14]1)[C:7](=[C:15]=[O:16])[C:6](=[CH:20][N:21]([CH3:23])[CH3:22])[C:5]2=[O:17]
Reactant: O=C=C1CC(=O)c2cc(Cl)ccc2N1C1CC1
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C=c1c(=O)c2cc(Cl)ccc2n(C2CC2)c1=C=O
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A solution of 6-chloro-1-cyclopropyl-carbonyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.996 g), N,N-dimethylformamide dimethyl acetal (3.808 g), and triethylamine (1.212 g) in benzene (16 ml) was refluxed with stirring for 30 minutes and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period of approximately 30 minutes. To the residue was added benzene (16 ml) and the solvent was distilled again. The residue was dissolved in ethyl acetate, treated with activated charcoal, and evaporated in vacuo. The residual solid was washed with diethyl ether to give 6-chloro-1-cyclopropyl-carbonyl-3-dimethylaminomethylene-4-oxo-1,2,3,4-tetrahydroquinoline (2.43 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14].C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]([CH3:31])[C:13]([C:15]1[S:30][C:18]2[C:19]3[CH:27]=[C:26]([C:28]([NH2:29])=[O:33])[CH:25]=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1)=[O:14]
Reactant: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C#N)ccc2OCC3)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C(N)=O)ccc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(2-chloro-4-(methylcarbamoyl)phenyl)-9-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 298 (100 mg) and potassium carbonate (37 mg) in DMSO (3 mL) at 0° C. was added hydrogen peroxide (30 μL of a 33% solution in water). The reaction was stirred at room temperature for 16 h. Water was then added and the resulting solid collected by filtration and air-dried to give 306. NMR: (DMSO): 2.81 (3H, d, J 4.5, Me), 2.91-2.93 (2H, m), 3.68 (3H, s, Me), 4.19-4.22 (2H, m), 6.41 (1H, s, NH), 7.03 (1H, d, J 8.4, Ar), 7.35 (1H, s), 7.71-7.77 (2H, m, Ar), 7.92 (1H, dd, J 8.3 and 2.0, Ar), 8.03-8.05 (3H, m) and 8.65-8.67 (1H, m). MS: (ESI+) MH+ 469.35
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.NC1C=CNN=1.[NH2:32][C:33]1[CH:37]=[C:36]([C:38]2[O:39][CH:40]=[CH:41][CH:42]=2)[NH:35][N:34]=1>O1CCCC1>[O:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[C:36]1[NH:35][N:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[NH:5][C:4]2=[O:13])[CH:37]=1
Reactant: O=C1Nc2ccc(Cl)cc2/C1=C/O
Reactant: Nc1cc(-c2ccco2)[nH]n1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1cc(-c2ccco2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and substituting 3-amino-5-(2-furyl)-pyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one is reacted with 0.280 gms. 3-amino-5-(2-furyl)-pyrazole by refluxing in tetrahydrofuran.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:10][C:9]([NH:11]C(=O)C)=[N:8][CH:7]=1)[CH3:4].Cl>CCO.O1CCOCC1>[ClH:1].[ClH:1].[CH3:2][N:3]([CH2:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1)[CH3:4]
Reactant: CC(=O)Nc1ncc(CN(C)C)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)Cc1cnc(N)s1
Temperature: 50 °C

Procedure:
Dissolved N-(5-dimethylaminomethyl-thiazol-2-yl)-acetamide hydrochloride (300 mg, 1.27 mmol) in 5 mL of EtOH. Added 2 mL of 4 M HCl in dioxane and heated at 50° C. for 16 h. LC-MS analysis indicated complete acetyl removal. Concentrated to give 5-dimethylaminomethyl-thiazol-2-ylamine dihydrochloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1CCOCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.5 %

Procedure:
To a solution of 1.63 g (12.5 mmol) of 2-(tetrahydro-pyran-4-yl)-ethanol in pyridine (15 mL) are added 3.58 g (18.8 mmol) of p-toluenesulfonylchloride. The reaction is stirred at room temperature for 5 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved 2M aqueous HCl solution (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are dried over Na2SO4, filtered and the solvent is removed to give 1.9 g of toluene-4-sulfonic acid 2-(tetrahydro-pyran-4-yl)-ethyl ester as off-white crystalline solid. Yield: 53%; ES-MS: m/z 285 [M+H]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (213 mg, 0.659 mmol) in tetrahydrofuran (10 mL) were added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (136 mg, 0.856 mmol) in tetrahydrofuran (0.5 mL) and triethylamine (200 mg, 1.98 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated and washed with ethyl acetate/hexane to give the title compound (222 mg, 77%) as a white powder. melting point 223° C.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([OH:43])=O)[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23].CCN(C(C)C)C(C)C.CNC>C(Cl)Cl>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]([C:41]([N:7]([CH3:8])[CH3:6])=[O:43])[CH:27]=[C:28]2[C:33]=1[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])[CH3:23]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
TSTU (108 mg, 0.36 mmol) was added portionwise to 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (115 mg, 0.36 mmol, as described in Example 3.00) and DIPEA (0.069 mL, 0.40 mmol) suspended in DCM (1 mL) at 25° C. under nitrogen. The resulting mixture was stirred at 25° C. for 1.5 hrs. Dimethylamine (0.180 ml, 0.36 mmol) was then added and stirring was maintained for an additional 30 min. The mixture was poured onto a silica gel column and purified by flash chromatography eluting with 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness. The residue was triturated in diethyl ether, collected by filtration and dried to afford 8-(1-hydroxyethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (123 mg, 0.355 mmol, 99%) as a off-white solid. Mass Spectrum: M+H+ 347.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27]CSCC1NC=NC=1Br)([O-:23])=[O:22].CN>>[N+:21]([CH:24]=[C:25]([NH:26][CH3:27])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[Br:1])([O-:23])=[O:22]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br
Reactant: NCCSCc1[nH]cnc1Br
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br

Procedure:
When 4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole (from the dihydrobromide (4.8 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) according to the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[2-((4-bromo-5-imidazolyl)methylthio)ethylamino]ethylene treated with methylamine by the procedure of Example 8(ii) there is produced 1-nitro-2-methylamino-2-[2-((4-bromo-5-imidazolyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.[Br:12][C:13]1[S:17][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][S:18]([C:16]2[S:17][C:13]([Br:12])=[CH:14][CH:15]=2)(=[O:20])=[O:19])=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: NS(=O)(=O)c1ccc(Br)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(Br)s1)c1ccc(Br)cc1Cl
Reaction time: 72 h

Procedure:
An 8 mL reaction vial is charged with 4-bromo-2-chlorobenzoic acid (0.39 mmol, 1.5 eq) and 2.0 mL of dichloromethane. A stock solution (4.0 mL) containing 5-bromothiophene-2-sulfonamide (0.26 mmol, 1 eq) and N,N-[dimethyl]-4-aminopyridine (48 mg, 0.39 mmol, 1.5 eq) in dichloromethane is added, followed by 0.261 g carbodiimide polystyrene resin (2.0 mmol/g, 0.52 mmol, 2.0 eq, Novabiochem) and the vial is capped and shaken. After 72 hr, 0.77 g sulphonated polystyrene resin (MP-TsOH) is added (1.53 mmol/g, 1.17 mmol, Argonaut). After about 18 hr the reaction mixture is filtered and concentrated under reduced pressure. Chromatography was applied to the residue and fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:8]([C:16]1[S:17][C@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C@H:21]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C@H:19]2[N:20]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:26][CH2:25][C@H:23]1[O:24][C@H:18]2[C@H:19]([N:20]=[C:16]([N:8]([C:9]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:15])[CH2:6][CH3:7])[S:17]2)[C@@H:21]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C@@H:22]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](CO)O[C@@H]2S1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](COS(C)(=O)=O)O[C@@H]2S1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Methanesulfonyl chloride (0.038 mL, 0.495 mmol) was added in portions to a stirred solution of tert-butyl ethyl(-(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate (0.190 g, 0.323 mmol) in dry pyridine (5 mL) at −20° C. After 3 h, the reaction mixture was diluted with DCM (20 mL) and the DCM extract was washed with satd. NaHCO3, brine, dried over Na2SO4 and concentrated. Residual pyridine was removed by co-evaporation with hexanes. The crude product was purified by silica gel column chromatography (3:7 EtOAc/hexanes) to give (-(3aR,5R,6S,7R,7aR)-2-((tert-butoxycarbonyl)(ethyl)amino)-6,7-bis((4-methoxybenzyl)oxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl methanesulfonate (0.215 g, 99.6%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 6.91-6.83 (m, 4H), 6.01 (d, J=6.88 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.60 (d, J=11.6 Hz, 1H), 4.52 (d, J=11.1 Hz, 1H), 4.42-4.36 (m, 2H), 4.27-4.23 (m, 3H), 3.96-3.84 (m, 2H), 3.8 (s, 3H), 3.79 (s, 3H), 3.55 (m, 2H), 2.98 (s, 3H), 1.52 (s, 9H), 1.20 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[C:4]([C:7](=O)[CH2:8][CH3:9])[CH:3]=1.[Cl:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1>>[Cl:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:7](/[C:4]2[CH:3]=[C:2]([Cl:1])[S:6][CH:5]=2)\[CH2:8][CH3:9])=[CH:17][CH:16]=1
Reactant: CCC(=O)c1csc(Cl)c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CC/C(=C(/c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1csc(Cl)c1
Yield: 26.4 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(5-chlorothiophen-3-yl)propan-1-one (1.5 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (2.0 g, 1.2 eq) to give 0.8 g desired product (45% yield, E).
Reaction SMILES: [C:1]([Si:5]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:36]([OH:40])(=[O:39])[CH:37]=[CH2:38]>C1(C)C=CC=CC=1>[C:36]([O:40][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 41.4 g (0.20 mol) of tert-butyldiisopropylchlorosilane, 60 ml of By toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 15.9 g (0.22 mol) of acrylic acid was added dropwise over one hour. After the completion of dropwise addition, the reaction solution was stirred for 2 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 42.9 g of a fraction having a boiling point of 80-83° C./0.27 kPa.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:33]=[CH:34][CH:35]=4)[O:27][CH2:28][C:29]([O:31]C)=[O:30])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:37].CCOCC>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:33]=[CH:34][CH:35]=4)[O:27][CH2:28][C:29]([O-:31])=[O:30])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:37]
Reactant: COC(=O)COc1cccc(C[C@@H]2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: O=C([O-])COc1cccc(C[C@@H]2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (+)-methyl [3-[[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl]phenoxy]acetate (1.92 g) in ethanol (30 ml) was added 1N-aqueous sodium hydroxide (4.1 ml). The reaction mixture was stirred for 1 hour at room temperature. Ether (50 ml) was added to the solution. The precipitated solid was collected by filtration to afford (+)-sodium [3-[[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl]phenoxy]acetate (0.83 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[C:15]2[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 59.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), 2-aminopyridine (51 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of dichloromethane under stirring. After stirring for 20 minutes, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.14 g, 0.54 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(pyridin-2-ylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 31a (0.1 g, yield 59%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10](Cl)[N:5]2[N:4]=1.C(O)(C)C.[CH2:22]([CH2:24][NH2:25])[OH:23]>O>[CH3:1][N:2]([C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10]([NH:25][CH2:24][CH2:22][OH:23])[N:5]2[N:4]=1)[CH3:17]
Reactant: CN(C)c1nc2nc3c(c(Cl)n2n1)SCCC3
Reactant: NCCO
Solvent: O
Solvent: CC(C)O
Product: CN(C)c1nc2nc3c(c(NCCO)n2n1)SCCC3

Procedure:
A mixture of 1.35 g (0,005 mole) of 2-dimethylamino-5-chloro-7,8-dihydro-9H-thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine, 5 ml of isopropanol and 0.61 g (0.01 mole) of ethanolamine is boiled for half an hour under stirring. 10 ml of water are added to the warm solution. The mixture is cooled, then the separated product is filtered and washed with water and cold isopropanol.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][CH2:7][CH2:6]O1)([CH3:3])[CH3:2].[BH4-].[Na+].C[CH2:12][OH:13]>>[CH2:4]([NH:8][CH2:7][CH2:6][CH2:12][OH:13])[CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)C1NCCO1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)CNCCCO
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-isopropyltetrahydro-1,3-oxazole (4.94 g, 38.2 mmol) in abs. EtOH (100 mL) at 0° C. was added NaBH4 (2.17 g (57.4 mmol, 1.5 equiv.) in small portions over 15 min. and the resulting mixture was stirred at room temp.overnight. The resulting mixture was concentrated under reduced pressure, then treated with EtOAc (150 mL) and water (100 mL) (CAUTION; gas evolution), and stirred at room temp for 30 min. The resulting organic layer was washed with a saturated NaCl solution. The combined aqueous layers were back-extracted with EtOAc (150 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford N-isobutyl-3-hydroxypropylamine as a colorless oil (5.04 g, 100%): 1H NMR (CDCl3) δ0.84 (d, J=6.6 Hz, 6H), 1.60-1.71 (m, 3H), 2.36 (d, J=6.6 Hz, 2H), 2.80 (dd, J=5.9, 5.9 Hz, 2H), 3.10-3.30 (br s, 2H), 3.74 (dd,, J=5.5, 5.5 Hz, 2H); 13C NMR (CDCl3) δ20.5, 28.1, 30.6, 50.0, 57.8, 64.1.