Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6]1)(=O)C.[CH2:12]([N:19]1[C:27]2[C:26](=[O:28])[N:25]([CH3:29])[C:24](=[O:30])[N:23]([CH3:31])[C:22]=2[N:21]=[C:20]1Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC(O)C>[CH2:12]([N:19]1[C:27]2[C:26](=[O:28])[N:25]([CH3:29])[C:24](=[O:30])[N:23]([CH3:31])[C:22]=2[N:21]=[C:20]1[N:7]1[CH2:6][CH:5]([OH:4])[CH2:11][NH:10][CH2:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Reactant: CC(=O)OC1CNCCNC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(nc(N3CCNCC(O)C3)n2Cc2ccccc2)n(C)c1=O
Yield: 97 %

Procedure:
[1,4]Diazepan-6-ol acetate (2B) (116 mg, 0.49 mmol) and 7-benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (100 mg, 0.33 mmol) were dissolved in 2-propanol (20 ml) and triethylamine (0.68 ml, 4.9 mmol) and the mixture was subjected to micro waves (150° C., 6 bar, 300 W, 8 hours). The solvents were evaporated and the remaining was redissolved in dichloromethane (20 ml) and water (20 ml). The aqueous layer was acidified with potassium hydrogen sulfate until pH=2. The aqueous layer was separated and aqueous sodium hydroxide was added until pH=12. The aqueous layer was extracted with 3×50 ml of dichloromethane, and the combined organic material were added excess trifluoroacetic acid, and evaporated, to afford 123 mg of the title compound as a brown oil in 75% yield.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:19]3[CH:24]=[C:23]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[S:22][C:20]=3[N:21]=2)=[CH:12][N:11]=1.[C:38](O)(=[O:42])[C@H:39]([CH3:41])[OH:40]>>[OH:40][C@@H:39]([CH3:41])[C:38]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:23]2[S:22][C:20]3[N:21]=[C:16]([C:13]4[CH:14]=[N:15][C:10]([NH:9][CH3:8])=[N:11][CH:12]=4)[N:17]=[C:18]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[C:19]=3[CH:24]=2)[CH2:27][CH2:28]1)=[O:42]
Reactant: C[C@H](O)C(=O)O
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCNCC4)sc3n2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(C(=O)[C@H](C)O)CC4)sc3n2)cn1

Procedure:
The crude TFA salt of N-methyl-5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)pyrimidin-2-amine was reacted with L-lactic acid via General Procedure B to give 28.3 mg of 388 after reverse phase HPLC purification. MS (Q1) 499.3 (M)+
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[O:14][CH3:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17]C(Cl)Cl.[OH-].[Na+].C(OCC)(=O)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][O:12][C:9]1[CH:8]=[C:7]([O:14][CH3:15])[C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:11][C:10]=1[CH:16]=[O:17]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(N2CCCC2)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(OC)c(N2CCCC2)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
Ex-38B: To a solution of 1-pyrrolidin-1-yl-2,4-dimethoxybenzene (Ex-38A, 1.82 g, 8.78 mmol) and α,α-dichloromethyl methyl ether (1.6 mL, 17.6 mmol) in dichloromethane (50 mL) was added titanium tetrachloride (1.0 M in dichloromethane, 26.3 mL, 26.3 mmol) dropwise at 0° C. The solution was allowed to stir for 16 h at ambient temperature and poured into ice/water. The aqueous solution was extracted with dichloromethane. The combined dichloromethane was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give a crude product (0.67 g). The aqueous solution was further treated with solid sodium hydroxide to pH 8. The suspension was mixed with ethyl acetate. The insoluble solid was removed by filtering through a pad of Celite. The filtrate was then partitioned. The aqueous solution was further extracted with ethyl acetate. The combined ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The combined crude product (1.71 g) was purified by flash chromatography. Elution with ethyl acetate and hexane (1:1, v/v) gave 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde as a brown oil (1.03 g, 50%): 1H-NMR (300 MHz, CDCl3) δ 10.25 (s, 1H), 7.26 (s, 3H), 6.44 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.20–3.16 (m, 4H), 1.93–1.89 (m, 4H). MS m/z: 235 (M+), 100%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>C(#N)C>[CH2:24]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1)[CH:25]([CH3:27])[CH3:26]
Reactant: Oc1c(C2CCNCC2)cccc1C(F)(F)F
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCC(c2cccc(C(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethyl)phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and isobutyl bromide (0.01 ml). MS m/z (relative intensity, 70 eV) 301 (M+, 4), 259 (13), 258 (bp), 238 (9), 194 (11).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[S:8][C:7]([CH:9]=O)=[N:6][CH:5]=1.[BH4-].[Na+]>>[CH3:1][NH:2][CH2:9][C:7]1[S:8][C:4]([CH3:3])=[CH:5][N:6]=1
Reactant: CN
Reactant: Cc1cnc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1ncc(C)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
Ti (OiPr)4 (1.3 eq) was added with stirring to MeNH2 (2.0 M in MeOH, 3 eq) under Ar. After 5 min. 5-methylthiazole-2-carbaldehyde (1 eq) was added, and the solution was stirred for 1-2 h. The reaction was cooled to 0° C. and NaBH4 (1.3 eq) was added. The solution was stirred at 0° C. to room temperature overnight. After quenching the reaction with water the mixture was filtered through Celite to remove the white ppt. MeOH was removed in vacuo and the residue was diluted with EtOAc. The resulting solution was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganic material was filtered off, and the solvent was removed in vacuo to give the crude product. Purification via column chromatography yielded N-methyl-1-(5-methylthiazol-2-yl)methanamine in 80-85% yield.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[CH3:31][S:32]([N:35]([C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][C@@H:51]2[CH2:53][O:52]2)[CH:44]=1)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:34])=[O:33]>C(Cl)(Cl)Cl.CO>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:53][C@H:51]([OH:52])[CH2:50][O:49][C:45]4[CH:44]=[C:43]([N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH:48]=[CH:47][CH:46]=4)=[CH:30][CH:29]=3)[CH2:17][CH2:16]2)=[O:19])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N(c1cccc(OC[C@@H]2CO2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1cccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccc(F)cc4)CC3)cc2)c1)S(C)(=O)=O

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide formate (0.591 g, 1.42 mmol) was reacted with tert-butyl methylsulfonyl{3-[(2S)oxiranylmethoxy]phenyl]carbamate (0.488 g, 1.42 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give tert-butyl 3-{[(2S)-3-({4-[(1-{[(4-fluorobenzyl)amino]carbonyl}-4-piperidinyl)amino]phenethyl}amino)-2-hydroxypropyl]oxy}phenyl(methylsulfonyl)carbamate which was dissolved in formic acid and stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol) to furnish the title compound (0.1 g, 0.163 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:24]([CH3:25])[CH2:23][CH2:22][CH:21]1[OH:26].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:21]([O:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:22][CH2:23][CH:24]1[CH3:25]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(C)CCC2O)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(C)CCC2OS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 250 mL round bottom flask was charged with 66.56D (mixture of diastereomers) (0.61 g, 1.7 mmol), DCM (10 mL), and TEA (0.28 mL, 2.0 mmol) and cooled to 0° C. To the cold solution was added methanesulfonyl chloride (available from Aldrich) (0.16 mL, 2.0 mmol) dropwise. The cooling bath was removed, and the mixture was stirred for 1 hour at ambient temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-40% EtOAc/hexane) to afford 66.56E (mixture of diastereomers) (0.69 g, 93% yield) as a colorless oil.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:40])/[C:17](/[CH3:39])=[CH:18]/[CH:19]=[C:20](\[CH3:38])/[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1>O1CCOCC1>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])[C:20]([CH3:38])=[CH:19][CH:18]=[C:17]([CH3:39])[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[C:9]([OH:10])=[O:8])=[O:40])([OH:30])=[O:29]
Reactant: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: CC(=CC=C(C)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCCC1C(=O)O
Yield: 16.7 %

Procedure:
Using General Procedure B with 1.14 g (2.09 mmol) (2E,4E)-(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid benzyl ester and with dioxane as solvent afforded 127 mg (16%) of the title compound as a white solid. MS m/e (%): 365 (M+H+, 100).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][C:35]=1[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cc(C(F)(F)F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.6 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-fluoro-5-trifluoromethylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.50 mg, 33.7% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.67 (m, 1H), 7.54 (m, 1H), 7.45 (m, 2H), 7.30-7.10 (m, 6H), 7.14 (d, 1H, J=7.4 Hz), 6.97 (apparent d, 1H, J=7.7 Hz), 5.37 (apparent dd, 1H, J=5.0, 8.5 Hz), 3.4 (m, 2H), 2.8 (m, 2H), 2.6 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.4 Hz), 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.1 Hz, overlapped); ESMS m/e: 542.6 (M+), 543.54 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][S:5][C:6]1[C:11]([CH:12]=O)=[C:10]([Cl:14])[N:9]=[C:8]([NH2:15])[N:7]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[S:5][C:6]2[N:7]=[C:8]([NH2:15])[N:9]=[C:10]([Cl:14])[C:11]=2[CH:12]=1)=[O:16]
Reactant: COC(=O)CSc1nc(N)nc(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc2c(Cl)nc(N)nc2s1
Temperature: 100 °C
Yield: 86.4 %

Procedure:
To a mixture of (2-amino-6-chloro-5-formyl-pyrimidin-4-ylsulfanyl)-acetic acid methyl ester (Preparation #22e, 0.20 g, 0.76 mmol) in dioxane (7.6 mL) was added K2CO3 (0.21 g, 1.5 mmol). The resulting mixture was heated at about 100° C. overnight, cooled to room temperature and water (1 mL) added to dissolve base. The remaining solid was filtered and washed with MeOH to give 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.16 g, 84%) as a pale yellow solid; RP-HPLC (Table 1, Method a) Rt 2.38 min; 1H NMR (d6-DMSO, 400 MHz) δ7.82 (s, 1H), 7.72 (br s, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[N:35]O)[NH2:34])=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:35]=[C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)[N:34]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)cc4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 56 mg (60% of theory)
Reaction SMILES: [F:1][C:2]1([F:15])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:18]1=[O:33].C(N(CC)CC)C>CN(C=O)C>[F:15][C:2]1([F:1])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[C:18]2=[O:33])[CH2:3]1
Reactant: O=C1C(Br)CCN1Cc1ccc(C(F)(F)F)cc1
Reactant: Oc1ccc(C2CCNCC2(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C(N2CCC(c3ccc(O)cc3)C(F)(F)C2)CCN1Cc1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
A mixture of 4-(3,3-difluoropiperidin-4-yl)phenol (200 mg, 0.94 mmol, E-2a from step D), 3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one (604 mg, 1.9 mmol), triethylamine (0.65 mL, 4.7 mmol), and 2 mL of DMF was heated in a microwave reactor at 120° C. for 1 h. The cooled reaction mixture was partitioned between water and 30 mL of ethyl acetate, and the aqueous phase was again extracted with 30 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 150 mg of 3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-benzyl)pyrrolidin-2-one (0.33 mmol, 35%, 2 diastereoisomers) which was purified and separated in step F. LCMS (method J) RT 0.8 min (60% AP), m/z 455.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Cc1cc(N)c(Cl)cc1F
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cc(C)c(F)cc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloro-4-fluoro-5-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])(O)=O.[Na+]>Br>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 105 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
3-(2-Chloro-4-methoxy-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 132, 48 mg) was dissolved in 48% aqueous HBr (0.9 m) and stirred at 105° C. (bath temperature) for 4 h. The reaction mixture was then poured on ice-water-brine and sat aq NaHCO3 and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting brown residue was purified by flash chromatography (8 g silica gel, ethyl acetate/heptane 1:4) to give the title compound as off-white semisolid (34 mg). MS (m/e)=364.0 (M−H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH2:42][CH3:43])=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=O)(C)(C)C.[C:46](O)([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[CH2:42]([C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([O:47][CH2:46][C:48]([F:51])([F:50])[F:49])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[C:40]([CH3:41])[CH:39]=1)[CH3:43]
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C)c(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-Ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M236) (176 mg, 0.28 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (43 mg, 29%).
Reaction SMILES: [Cl-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[OH:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>C1COCC1>[CH3:18][C:17]1[C:10]2[O:9][CH2:2][CH:12]([OH:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1
Reactant: C[S+](C)(C)=O
Reactant: Cc1cccc(C=O)c1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2c1OCC2O

Procedure:
Under a nitrogen atmosphere 0.945 g (7.35 mmol) trimethylsulphoxonium chloride were placed in 20 mL THF and combined batchwise with 0.300 g (7.50 mmol) sodium hydride (55%, suspension in mineral oil). The reaction mixture was refluxed for 2 h. Then 1.00 g (7.35 mmol) 2-hydroxy-3-methylbenzaldehyde in 20 ml. THF were added dropwise to the reaction mixture and refluxed overnight. Then PE was added and the suspension obtained was filtered. The filtrate was evaporated down i.vac. and purified by flash chromatography. The fractions containing the product were combined and evaporated down.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([NH2:10])=O)=[C:5]([CH3:11])[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[P].O(Cl)Cl.ClC(Cl)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]([CH2:7][C:8]#[N:10])=[C:5]([CH3:11])[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccc2)c(C)c1CC(N)=O
Agent: ClOCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1nn(-c2ccccc2)c(C)c1CC#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
6 grams 3,5-dimethyl-1-phenyl-pyrazol-4-acetamide, 2.5 grams phosphorus-oxychloride and 9 milliliters dichloroethane were mixed and stirred for 2 hours at 100° C.) The reaction mixture was poured on ice, diluted by the addition of chloroform and neutralized by the addition of aqueous sodium hydroxide. The organic phase was separated, washed with water, dried and the solvent evaporated. 3,5-Dimethyl-1-phenyl-pyrazol-4-acetonitrile, melting at 69°-70° C., was obtained in a yield of 82%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCCCOc1ccccc1-c1ccccc1
Product: COC(=O)c1cc(OCCCOc2ccccc2-c2ccccc2)cc(OCCCOc2ccccc2-c2ccccc2)c1

Procedure:
Using this procedure, the reaction of 3,5-dihydroxybenzoic acid methyl ester with 2-(3-bromopropoxy)-1,1-biphenyl gave 3,5-bis[3-(1,1'-biphenyl-2-yloxy)propoxy]benzoic acid methyl ester, mp 77°-79°. Anal. Calcd for C38H36O6 : C, 77.53; H, 6.16. Found: C, 77.31; H, 6.15.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[C:18]([C:20]1[N:24]([CH3:25])[C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]=1)=[O:19].[H-].[Na+].[CH3:32][CH:33]([SH:35])[CH3:34]>O1CCCC1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([S:35][CH:33]([CH3:34])[CH3:32])=[C:3]([C:18]([C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=3)=[O:19])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(=O)c3nc4ccccc4n3C)sc21
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(C(=O)c3nc4ccccc4n3C)sc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Prepared according to the method described in Example 37 step d from 5-bromo-3-methyl-6-[(1-methyl-1H-benzimidazol-2-yl)carbonyl]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.2 g), sodium hydride (0.12 g) and 2-propanethiol (0.26 ml) in dry tetrahydrofuran (150 ml) with stirring at room temperature for 19 hours. The residue was purified by flash silica chromatography eluting with a gradient of 20-50% ethyl acetate in isohexane to give the title compound as a yellow solid (0.92 g).
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:6]([O:5][P:4]([C:3]([C:1]#[N:2])=[CH:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:11])[O:8][CH2:9][CH3:10])[CH3:7]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C(C#N)=CC1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of diethyl cyanomethylphosphonate (32.6 g, 184 mmol), ammonium acetate (6.0 g, 78 mmol), acetic acid (6 mL) in toluene (120 mL) was added cyclohexanecarboxyaldehyde (21 g, 174 mmol). The reaction mixture was stirred at room temperature for two days and then heated at 100° C. for 3 hours. After cooling, the reaction mixture washed with saturated sodium bicarbonate solution three times, with brine one time and then dried over magnesium sulfate. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield [1-cyano-2-(cyclohexyl)-vinyl]-phosphonic acid diethyl ester as a light brown oil.