Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:40])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH3:38])[C:35](=[O:39])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].[CH3:41][C:42]([CH3:46])([CH3:45])[CH2:43][NH2:44]>O>[C:8]([O:12][C:13](=[O:40])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:39])[NH:44][CH2:43][C:42]([CH3:46])([CH3:45])[CH3:41])[CH3:38])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)(C)CN
Agent: Oc1ccccn1
Solvent: O
Product: C[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
25 mg of 2-hydroxypyridine (0.26 mmol) was added to a solution of 250 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (76i) (0.52 mmol) in (2,2-dimethylpropyl)amine (1.22 ml) (10.4 mmol), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/acetone=5/2-1/1) to obtain 283 mg of the title compound (yield: 96%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][C:18]([CH3:23])([CH3:22])[CH2:17]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][O:19][C:18]([CH3:23])([CH3:22])[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC(C)(C)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC(C)(C)C3)c2n1
Yield: 78.8 %

Procedure:
A solution of 2-butyloxy-9-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]-8-methoxy-9H-purin-6-amine (161 mg) in methanol (1 mL) was treated with 4N HCl in 1,4-dioxane (0.5 mL) for 1 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried to give the title compound (122 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]#[N:24]>>[CH2:11]([O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:23]([NH2:24])[C:22]([CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH3:13])=[CH:4]2)[CH3:12]
Reactant: CCOc1ccc(N)c(C=O)c1
Reactant: COc1ccccc1CCC#N
Product: CCOc1ccc2nc(N)c(Cc3ccccc3OC)cc2c1

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-ethoxybenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][Cl:22])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(OCCCCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
2.9 g of 4-(4-phenylbutyloxy)benzyl alcohol were dissolved in 30 ml of chloroform, and 1.6 g of thionyl chloride were further fed dropwise to the resultant solution. The solution was then stirred for 1 hour at room temperature. After completed the reaction, the solution reacted was poured into ice-water and extracted with chloroform. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 3.2 g of 4-(4-phenylbutyloxy)benzyl chloride.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:8](=[O:18])[C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH3:19]O>[Zn].C1(C)C=CC=CC=1>[CH3:19][O:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:18])=[C:7]([CH3:6])[CH:16]=1
Reactant: CO
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(O)c2ccccc12
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 81 %

Procedure:
4.9 g of concentrated sulfuric acid were added dropwise to a stirred mixture of 4.75 g (27.6 mmole) of 2-methyl-1,4-naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of methanol and 15 mL of toluene, in an ice bath. After the addition was complete, the reaction mixture was stirred for 4.5 hours at 60° C. The reaction product was extracted with ethyl acetate, washed with water then brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to yield 4.25 gm (81% yield) of the title compound as an off-white powder having a melting point of 102-103° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ 2.38 (s, 3H), 3.91 (s, 3H), 6.76 (s, 1H), 7.42(m, 2H), 8.04 (d, 1H, J=8.1 Hz), 8.14 (d, 1H, J=8.1 Hz), 8.50(bs, 1H). The mass spectrum showed a molecular ion at m/z 188.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:28]([OH:30])=O)[CH:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:28](=[O:30])[NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][CH:13]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1SC(c1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1C(=O)Nc2ccccc2SC1c1ccccc1)OCc1ccccc1
Reaction time: 5 h

Procedure:
1.0 g of N-benzyloxycarbonyl-S-(2-aminophenyl)-β -phenylcysteine was mixed with 0.5 g of dicyclohexylcarbodiimide and 15 ml of N,N-dimethylformamide and the resulting mixture was stirred for 5 hours. After the mixture was concentrated under reduced pressure, 20 ml of ethyl acetate was added to the residue and the insoluble matter was removed. Thereafter, the solution was concentrated to obtain the desired compound, or 3-benzyloxycarbonylamino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. The physical properties of this product agreed with those of the compound obtained in Example 2.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[S:13][C:14]([C:17]([NH2:19])=[O:18])=[C:15]([NH2:16])[C:7]=12)(=[O:5])[CH3:4]>CO>[NH2:16][C:15]1[C:7]2[C:8](=[N:9][C:10]([CH3:12])=[CH:11][C:6]=2[CH:3]([OH:5])[CH3:4])[S:13][C:14]=1[C:17]([NH2:19])=[O:18]
Reactant: CC(=O)c1cc(C)nc2sc(C(N)=O)c(N)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(C)O)c2c(N)c(C(N)=O)sc2n1
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A spatula tip full of NaBH4 was added to a solution of 9.9 mg 4-acetyl-3-amino-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide in 1 mL MeOH. After 0.5 h, the reaction was concentrated in vacuo, quenched with aqueous NH4Cl, extracted 4 times into EtOAc, concentrated in vacuo, dissolved in MeOH—CH2Cl2, filtered, concentrated and dried in vacuo at 60° C. to provide 8.1 mg of the title compound as a beige solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH:8]1[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1
Reactant: COCCCOC(c1ccccc1F)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOC(c1ccccc1F)C1CCCNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 3-((3-methoxypropoxy)(2-fluorophenyl)methyl)piperidine-1-carboxylate (28.0 mg, 0.07 mmol) was dissolved in 4 N HCl in dioxane. The resulting solution was stirred at rt until no starting material was left (˜30 min). The solvent was removed in vacuo to give 3-((3-methoxypropoxy)(2-fluorophenyl)methyl)piperidine hydrochloride as an oil. MS ESI+ve m/z 282 (M+1).
Reaction SMILES: [CH2:1]([C@:8]([OH:24])([CH2:21][CH2:22]O)[C:9]([NH:11][C@H:12]([C:17](=[O:20])[NH:18][CH3:19])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:46])[NH:28][C@H:29]([C:34]([NH:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)=[O:35])[C:30]([CH3:33])([CH3:32])[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:25][O:26][C:27](=[O:46])[NH:28][CH:29]([C:34]([NH:36][N:37]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)[CH2:22][CH2:21][C:8]([C:9](=[O:10])[NH:11][CH:12]([C:17](=[O:20])[NH:18][CH3:19])[C:13]([CH3:16])([CH3:14])[CH3:15])([OH:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:35])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)N[C@H](C(=O)NNCc1ccc(Br)cc1)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)[C@@](O)(CCO)Cc1ccccc1)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNC(=O)C(NC(=O)C(O)(CCN(Cc1ccc(Br)cc1)NC(=O)C(NC(=O)OC)C(C)(C)C)Cc1ccccc1)C(C)(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
A mixture of (2S)-2-Benzyl-N-((1S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-2,4-dihydroxy-butyramide (52S) (0.337 g, 1.00 mmol), IBX (0.560 g, 2.0 mmol) and 10 mL 1,2-dichloroethane in a reaction vial sealed with a screw cap was heated at 80° C. for 2 h. The resulting suspension was transferred to a 20 mL syringe and filtered through a syringe filter into a solution of hydrazide (9) (0.372 g, 1.00 mmol) in 15 mL DCE in a flame dried 50 mL round-bottom flask equipped with a septum. To this was added acetic acid (0.12 mL 2.0 mmol), mixture was stirred for 10 min and then sodium triacetoxyborohydride (0.636 g, 3.0 mmol) was added. The septum-sealed flask was flushed with nitrogen and the reaction was stirred at room temperature for 24 h. The reaction was quenched by addition of water and volatiles were evaporated. The residue was dissolved in 50% MeCN/water and purified by preparative RP-LC-MS (repeated 1 mL injections) to give 0.191 g of the title compound (28% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([C:18](=O)[CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>ClCCCl.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:17]([C:18](=[N:28][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: CCCC(=O)c1ccc2c(ccn2C)c1OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC(=NC(C)(C)C)c1ccc2c(ccn2C)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)butan-1-one (0.260 g, 0.85 mmol) in DCE (4 mL) was added t-BuNH2 (0.40 mL, 3.79 mmol). The mixture was cooled to 0° C. before TiCl4 solution (1M DCE, 0.55 mL, 0.55 mmol) was added dropwise via syringe pump over 30 min. The reaction was allowed to warm to room temperature and then heated at 50° C. for 6 h. The mixture was then diluted with DCM (15 mL) and quenched with NaHCO3 (aqueous saturated, 5 mL). Upon vigorous shaking, the organic phase was separated using a PTFE phase separator and dried over Na2SO4. Removal of the solvent afforded N-(1-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)butylidene)-2-methylpropan-2-amine as a yellow oil, which was taken directly into next step without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)([O-:17])=[O:16]
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: Cc1cc(Nc2cccc([N+](=O)[O-])c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-nitroaniline (34 mg, 0.243 mmol) similar to Example 11 as a yellow solid (65 mg, 87%). 1H NMR (DMSO-d6): 10.17 (s, 1H), 9.18 (s, 1H), 8.77 (d, J=4.8 Hz, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.98 (t, J=6.9 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.63 (t, J=8.3 Hz, 1H), 7.55–7.51 (m, 1H), 6.74 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].[Cl-].[NH4+:37]>>[F:33][C:30]([F:31])([F:32])[CH2:29][N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([C:10]5[CH:9]=[N:8][N:7]([C:2]([CH3:1])([CH3:6])[C:3]([NH2:37])=[O:4])[CH:11]=5)[CH:35]=[CH:34][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1
Reactant: [NH4+]
Reactant: CC(C)(C(=O)O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Agent: [Cl-]
Product: CC(C)(C(N)=O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 240, 2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionic acid was reacted with ammonium chloride to give 288. MS (ESI+) 504.1. 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.3-8.25 (m, 2H), 8.04 (s, 1H), 7.51 (dd, J=8.3, 1.5, 1H), 7.40 (d, J=1.4, 1H), 7.16 (br, 1H), 6.77 (br, 1H), 5.86 (q, J=8.7, 2H), 4.40 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 1.74 (s, 6H)
Reaction SMILES: II.[C:3]1([C:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2[N:15]=[C:14]([CH:16]=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[K].[CH3:31][OH:32]>>[CH3:31][O:32][C:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:9]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:15]=1)=[O:17]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cccc(C=O)n1
Reactant: CO
Agent: II
Agent: [K]
Product: COC(=O)c1cccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h

Procedure:
A solution of 8.15 g of iodine in 148 ml of methanol is instilled in a solution of 18.29 g of 6-(diphenyl-tert-butylsilyloxymethyl)-2-pyridinecarbaldehyde and 7.22 g of potassium hydroxidelin 593 ml of methanol at 0° C. under nitrogen. After 1 hour of stirring, iodine solution was again.added and subsequently stirred, and this was also repeated until a complete reaction was discernible in the thin layer. The reaction mixture is concentrated by evaporation in a vacuum up to about 60 ml, mixed with 100 ml of semiconcentrated sodium chloride solution and extracted four times with ether. The combined organic phases are washed once with 60 ml of saturated sodium thiosulfate solution, semiconcentrated sodium. chloride solution, dried on sodium sulfate and after filtration, concentrated by evaporation in a vacuum. 19.4 g of the title compound is obtained, which is further used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10](=[O:12])[NH2:11])=[O:4].[OH-].[Na+]>CO>[C:10]([C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])(=[O:12])[NH2:11]
Reactant: COC(=O)c1sccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccsc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A solution of 3-carbamoyl-thiophene-2-carboxylic acid methyl ester (125 mg, 0.67 mmol) in methanol (2.0 mL) at 25° C. was treated with a 1N aqueous sodium hydroxide solution (2.0 mL, 2.02 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (10 mL) and then acidified to pH=2 with a 1N aqueous hydrochloric acid solution. The resulting slurry was cooled to 0° C. The solids were collected by filtration, washed with water, and dried in vacuo to afford 3-carbamoyl-thiophene-2-carboxylic acid (102 mg, 88.3%) as an off-white solid: LR-MS for C6H5NO3S (M−H)+ at m/z=170.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.[N:19]1([O:28][C:29](N(C)C)=[N+](C)C)[C:23]2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CNOC>CN(C)C=O.O>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:19]([O:28][CH3:29])[CH3:23])=[O:5]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Cl)nc1Cl
Reaction time: 1.5 h
Yield: 49.3 %

Procedure:
To a solution of 2,6-dichloronicotinic acid (500 mg, 2.63 mmol, Aldrich 90%) in anhydrous N,N-dimethylformamide (5 mL) were added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.28 g, 3.37 mmol, Aldrich), 1-hydroxybenzotriazole hydrate (456 mg, 3.37 mmol, Aldrich) followed by N,N-diisopropylethylamine (1.3 g, 10.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (306 mg, 3.15 mmol, Aldrich) at 0° C. The reaction was stirred for 1-2 hrs, treated with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated. The crude product was purified on silica gel with hexanes/ethyl acetate to give 2,6-Dichloro-N-methoxy-N-methyl-nicotinamide as a white solid (304.5 mg, 50% yield). HRMS, observed: 233.9968, Calcd for M+: 233.9963
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:24][CH:25]=1.FC(F)(F)C1C=CC(C(N)=S)=CC=1.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)[S:24][CH:25]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: NC(=S)c1ccc(C(F)(F)F)cc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(F)(F)F)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 4-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (prepared from 4-trifluoromethyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in acetonitrile in the presence of cesium carbonate to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)SC)([O-:3])=[O:2].N[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(O)C>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCCCO
Solvent: CCO
Product: O=[N+]([O-])C=C(CCCCCO)CCCCCO

Procedure:
Heating 1-nitro-2,2-bis(methylthio)ethylene with an excess of 5-aminopentan-1-ol in ethanol gives 1,1-bis(5-hydroxypentyl)-2-nitroethylene, which may be treated with p-toluenesulphonyl chloride in pyridine and the product heated with thiourea in acetone to give 1,1-bis(5-(S-isothioureido)pentyl)-2-nitroethylene.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CO
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 118.7 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (2.0 g, 7.1 mmol) and 4-piperidin-4-yl-morpholine (1.4 g, 8 5 mmol) in DCE (40 mL) was stirred at room temperature for 1.5 hour then triacetoxyborohydride (2.2 g, 10.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (70 g). The cartridge was washed with MeOH/DCM (1/1: v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1: v/v). The solvents were removed and the residue was triturated in hot IMS, filtered and dried at 60° C. for 1 hour under vacuum to give 2-Chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as a white solid (2.6 g, 84%). LCMS (Method C): RT 0.34 min and 1.67 min; [M+H]+ 438
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].C[O-].[Na+].[F:23][C:24]([F:29])([F:28])CCI.O>CO>[O:17]1[C:13]2([CH2:18][CH2:19][CH:10]([CH:5]([S:4][CH2:1][CH2:2][C:24]([F:29])([F:28])[F:23])[C:6]([O:8][CH3:9])=[O:7])[CH2:11][CH2:12]2)[O:14][CH2:15][CH2:16]1
Reactant: COC(=O)C(SC(C)=O)C1CCC2(CC1)OCCO2
Reactant: FC(F)(F)CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(SCCC(F)(F)F)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4.27 g of methyl 2-(acetylthio)-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetate in 30 ml of methanol was added 3.14 g of a 28% solution of sodium methoxide in methanol at 0° C. under a nitrogen atmosphere. To the mixture was added 4.31 g of 3,3,3-trifluoro-1-iodopropane, and the mixture was stirred at room temperature for 1 hour and then at 70° C. for 1 hours. The reaction mixture was cooled to room temperature, and 100 ml of water was added thereto. The mixture was concentrated to a total amount of about 100 ml under reduced pressure, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 100 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.60 g of methyl 2-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(3,3,3-trifluoropropylthio)acetate (hereinafter, referred to as the present compound (8)) represented by the formula: