Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH3:31])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=1)=[O:9].[CH2:41]1COCC1.[N+](=C)=[N-]>C(OCC)C>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:34]=1)[CH2:6][N:7]([CH3:31])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:41])=[O:29])=[CH:24][CH:23]=1)=[O:9]
Reactant: C1CCOC1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(C(=O)O)cc2)c2cccnc2c(=O)n1C
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(C)c(=O)c3ncccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of the compound obtained in Example 74 (50 mg) and THF (15 ml) was added a solution of diazomethane (excess) in ethyl ether. After the mixture was stirred for 30 minutes at room temperature, the solvent was evaporated to give the titled compound as colorless crystals (25 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].N1(CC2(C3C=CC(OCCCN4CCOCC4)=CC=3)CCOCC2)CCOCC1>>[CH3:1][NH:2][CH2:3][C:5]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:15][CH:16]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CNC(=O)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNCC1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Yield: 77 %

Procedure:
The title compound (252 mg, 77%) was prepared from N-methyl-4-[4-(3-morpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide and a solution of LiAlH4 (10M solution in Et2O) similarly to the procedure used for 4-(3-{4-[4-(morpholin-4-ylmethyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)morpholine. 1H NMR (400 MHz, CD3OD) δ 1.85-2.00 (m, 6H), 2.12 (m, 2H), 2.24 (s, 3H), 2.45 (m, 4H), 2.53 (t, 2H), 2.63 (s, 2H), 3.57 (m, 2H), 3.70-3.80 (m, 6H), 4.01 (t, 1H), 6.88 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 349.2477 [MH]+.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[C:20]([CH3:40])=[C:19]1[CH3:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH3:40])=[C:19]1[CH3:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 65.6 %

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-3,4-dimethyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 192, 3.15 g, 5.15 mmol) following the procedure described for Intermediate 18. Two silica gel chromatography (0%-100% ethyl acetate/hexanes) afforded the desired product as a white foamy solid (1.68 g, 65.6%).
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]([CH3:21])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=O)C.[OH-].[K+].Cl.C(=O)=O>C(OCC)(=O)C.CCCCCC.C(O)(=O)C.O.C(O)CO>[CH3:21][C:8]1[NH:7][CH:6]=[C:10]([CH3:11])[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1[nH]c(C)c(-c2ccc(C(=O)O)cc2)c1C
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: OCCO
Product: Cc1c[nH]c(C)c1-c1ccc(C(=O)O)cc1
Temperature: 98 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
4-(4-Carboxy-phenyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (11.8 g), 11.8 mL of ethylene glycol, 36 mL of water and 13.6 mL of 9 N potassium hydroxide were refluxed at 105° C. for 25 minutes. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed conversion of all starting material at Rf 0.5 to a new product at Rf 0.3. The mixture was cooled to 98° C. and 13 mL of 10 N hydrochloric acid was added to a pH of 2.0 accompanied by rapid release of carbon dioxide gas. The maximum temperature reached was 103° C. which dropped to 95° C. by the end of the gas evolution. The mixture was cooled in an ice bath and vigorously stirred for 30 minutes. The solids were collected by vacuum filtration and washed three times with 20 mL of water each time to give 8.7 g (99% yield) of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-benzoic acid as a light purple solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.00, 2.18 (2×s, 2×3H, 2×CH3), 6.46 (s, 1H, pyrrole CH), 7.34, 7.90 (multiplets, 4H, aromatic), 10.49 (br s, 1H, NH), 12.70 (br s, 1H, COOH). MS m/z 216 [M+1].
Reaction SMILES: NC1C=CC=CC=1NC[N:10]1[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1=[O:18].C(=O)CC.C(O)(=O)C>O1CCOCC1>[CH2:15]([CH:13]1[CH2:14][NH:10][C:11](=[O:18])[CH2:12]1)[CH2:16][CH3:17]
Reactant: CCCC1CC(=O)N(CNc2ccccc2N)C1
Solvent: C1COCCO1
Solvent: CCC=O
Solvent: CC(=O)O
Product: CCCC1CNC(=O)C1
Temperature: 25 °C
Yield: 33 %

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of (2-aminophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a29 (1 eq, 0.69 mmol, 170 mg), propionaldehyde (1.4 eq, 0.966 mmol, 56 mg, 71 μl), acetic acid (0.3 ml) and dioxane (4 ml) was heated at 65° C. during 40 h. After cooling to room temperature, the solvent was removed under vacuum and the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4) to give of 1-[(2-propyl)-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 94 (65 mg, 33%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)(=[O:17])=[O:16])[C@@H:10]([CH3:28])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:28][C@H:10]1[CH2:9][NH:8][CH2:14][CH2:13][CH2:12][N:11]1[S:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][CH:22]=[CH:21]2)(=[O:17])=[O:16]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2cnccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CNCCCN1S(=O)(=O)c1ccc2cnccc2c1
Yield: 48.3 %

Procedure:
1.1 g of (S)-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline was dissolved in 50 mL of dichloromethane, and 1.8 mL of trifluoroacetic acid was added dropwise thereto at room temperature and then reacted for 6 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane (50 mL×2). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol:28% ammonia water=10:1:0.05) to obtain 0.4 g of the compound of interest as a white crystal (48%).
Reaction SMILES: [NH:1]([C:24]([O:26]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].Cl.N[C@H](C(N[C@H](C(OCC=C)=O)CC1C=CC=CC=1)=O)[C@H](CC)C.[N:55]1([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:62][CH2:61][CH2:60][C@H:56]1C(O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:55]1([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:62][CH2:61][CH2:60][C@H:56]1[C:24]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:26]
Reactant: C=CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C=CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)[C@@H](C)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](C)CC
Yield: 73 %

Procedure:
After cleavage of the Boc group from Boc-Ile-Phe-Oallyl according to general procedure D, the HCl salt of Ile-Phe-Oallyl was coupled to Boc-Pro in DMF (60 ml) via general procedure C, by using TEA (1.94 ml, 13.9 mmol), HOBt (3.047 g, 19.9 mmol), and EDCl (2.79 g. 14.6 mmol). After workup, the product was crystallized from cold EthOAc to give the title compound in 73% yield as a white solid. Rf=0.30 (50% EthOAc/hexane). [α]D23=−60.5 (c 0.585, CHC3). FABMS (C28H41N3O6) found 516.3 (M+H+).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][CH2:13]O.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([C:7]([O:9][CH2:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCO
Reactant: O=C(O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.4 %

Procedure:
To a mixture of cyclohexanecarboxylic acid (1.28 g, 10 mmol), 2-(trimethylsilyl)ethanol (1.3 g, 11 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.11 g, 11 mmol) in dichloromethane was added 4-dimethylaminopyridine (123 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 3 d. It was partitioned between ethyl acetate and 2N HCl. The organic phase was washed with brine, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuuo. The residue was purified by flash chromatograph on silica gel (eluting with 0-20% ethyl acetate in hexane) to provide the title compound as a colorless oil (1.7 g, 75% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][Si](C)(C)C.C([Li])(CC)C.[CH3:13][C:14]12[C:22](=O)[C:18]([CH3:24])([CH2:19][CH2:20][CH2:21]1)[CH2:17][N:16]([CH3:25])[CH2:15]2.[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1CCCCC1>[CH3:13][C:14]12[C:22](=[CH:3][O:2][CH3:1])[C:18]([CH3:24])([CH2:19][CH2:20][CH2:21]1)[CH2:17][N:16]([CH3:25])[CH2:15]2
Reactant: COC[Si](C)(C)C
Reactant: CN1CC2(C)CCCC(C)(C1)C2=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COC=C1C2(C)CCCC1(C)CN(C)C2
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
100 ml of a solution of 20.5 ml of (methoxymethyl)trimethylsilane in dry tetrahydrofuran was cooled under a nitrogen atmosphere. Then 92 ml of a 1.3 M solution of s-butyllithium in cyclohexane was added dropwise thereinto at −78° C. After the completion of the addition, the mixture was stirred at −35° C. for 30 minutes. After adding 10.9 g of 1,3,5-trimethyl-3-azabicyclo[3.3.1]nonan-9-one, the resulting mixture was stirred at room temperature for 2 hours and then poured into a cooled aqueous solution of ammonium chloride. Then it was made alkaline by adding potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 9.2 g of the title compound was obtained as a pale-brown oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]2[O:24][CH2:25]C(=O)[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([O:33][CH3:34])([O:31][CH3:32])OC.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]2[O:24][CH2:25][C:28]([O:31][CH3:32])([O:33][CH3:34])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)OC
Reactant: O=C1COC2C(OCc3ccccc3)CN(C(=O)OCc3ccccc3)C12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)COC2C(OCc3ccccc3)CN(C(=O)OCc3ccccc3)C21
Temperature: 60 °C

Procedure:
Compound 12a (7.6 g) was dissolved dry methanol (100 mL). Trimethyl orthoformate (30 mL) and pTsOH (0.2 g) was added at rt under a nitrogen atmosphere. The mixture was heated at 60° C. for 8 hours. Once the reaction was deemed complete according to TLC, it was cooled to rt and concentrated in vacuo. The crude product was purified by column chromatography over silica gel eluting with ethyl acetate-heptane (1:4) to afford after concentration in vacuo the ketal 12b as a clear oil (5.9 g, 71% over 2 steps); ESI+, m/z: 382 (M+ —OMe).
Reaction SMILES: [ClH:1].[CH3:2][C:3]([CH3:11])([CH2:7][N:8]([CH3:10])[CH3:9])[C:4](O)=[O:5]>S(Cl)(Cl)=O>[ClH:1].[CH3:2][C:3]([CH3:11])([CH2:7][N:8]([CH3:10])[CH3:9])[C:4]([Cl:1])=[O:5]
Reactant: CN(C)CC(C)(C)C(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CN(C)CC(C)(C)C(=O)Cl

Procedure:
A mixture of 2,2-dimethyl-3-dimethylaminopropionic acid hydrochloride (1.76 g, 0.00969 mole) and thionyl chloride (10 ml) was heated under reflux for 30 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[C:11]1([CH3:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:14][CH:11]1[CH2:13][CH2:12]1
Reactant: CC1(Br)CC1
Reactant: Oc1ccc(F)cc1Br
Product: Fc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-fluoro-phenol and commercially available bromo-methyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[CH:28]2.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[N:29]=[CH:28]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc2c(cnn2C2CCCCO2)c1
Yield: 94 %

Procedure:
3,4-dihydro-2H-pyran (0.84 ml, 9.21 mmol) and pyridinium p-toluenesulfonate (202 mg, 0.804 mmol) were added to a solution of 5-bromo-1H-indazole (790 mg, 4.01 mmol) in methylene chloride (15 ml) at room temperature, and the resulting mixture was refluxed for 6 hours. Then, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=93/7) to obtain 5-bromo-1-tetrahydro-2H-pyran-2-yl-1H-indazole (1.06 g, 94%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O>[S:13]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2cccnc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cccnc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
To a solution of compound 147-B (0.508 g, 2.63 mmol) in a mixture of MeOH (15 mL) and H2O (3 mL) was added 3N NaOH (1.9 mL, 5.66 mmol) and the reaction mixture was stirred at ambient temperature for 5 h. The solvent was evaporated under reduced pressure, the residue dissolved in H2O, and acidified with 1N HCl. The precipitate was filtered, washed with H2O, and dried under vacuum to afford compound 147-C as a white solid (0.366 g, 78%). MS: m/z 180.0 (MH+).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CCO>[C:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:26])[F:27])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (Example 1, 0.200 g, 0.53 mmol) was taken into EtOH (5 mL) and cooled to 0° C. where was added NaBH4 (0.020 g, 0.53 mmol). The ice bath was removed and the reaction was allowed to stir at room temperature overnight. The EtOH was removed and water was added to the resulting material, where it was extracted with methylene chloride, dried over sodium sulfate and concentrated. The product was purified via column chromatography using 15% ethyl acetate in hexane as the eluent to afford 0.194 g of desired product as a white solid. MS (ESI) m/z 380 ([M+H]+); Anal. Calcd for C23H16F3NO: C, 72.82; H, 4.25; N, 3.69. Found: C, 72.52; H, 4.20; N, 3.55.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.[OH-].[Na+]>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[OH:20])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC1CCN(CCCC(O)c2ccccc2)CC1)c1ccccc1
Reaction time: 2 h

Procedure:
4-Benzamido-(4-phenyl-4-oxobutyl)piperidine (3.4 g.) was dissolved in methanol (125 ml.) and a solution of sodium borohydride (6.0 g.) in 0.2N sodium hydroxide (30 ml.) was added at room temperature over a period of 0.5 hours. The resulting mixture was stirred for a further 2 hours and then heated under reflux for 4 hours. The resulting mixture was filtered, the filtrate evaporated almost to dryness and then treated with water (100ml.). The colourless solid was filtered off, washed with water, dried, dissolved in a small amount of ethanolic hydrogen chloride and treated with ether until crystallisation commenced. Filtration and drying gave 1.875 g. of the hydrochloride of the title compound, m.p. 221° C. (Found: C, 68.1; H, 7.4; N, 7.3. C22H28N2O2.HCl requires C, 67.9; H, 7.5; N, 7.2%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:8]2.[Br:22][C:23]([CH3:28])([CH3:27])[C:24](Br)=[O:25]>>[Br:22][C:23]([CH3:28])([CH3:27])[C:24]([N:11]([CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=[O:25]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=[N+]([O-])c1ccccc1NNC1C2CC3CC(C2)CC1C3
Product: CC(C)(Br)C(=O)N(Nc1ccccc1[N+](=O)[O-])C1C2CC3CC(C2)CC1C3

Procedure:
1-(Adamantan-2-yl)-2-(2-nitrophenyl)hydrazine prepared in Processes 1 and 2 in Example 180 and 2-bromoisobutyryl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and 2-bromo-N-(adamantan-2-yl)-2-methyl-N′-(2-nitrophenyl)propane hydrazide was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(N)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)c1ccnc(N)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
1-(2-aminopyrimidin-4-yl)ethanone (Compound 3a) (0.5 g) was dissolved in 50 mL methanol and cooled to 0° C. Sodium borohydride (0.138 g) was added portion wise and the mixture was stirred for 16 hours at room temperature. Saturated ammonium chloride solution (20 mL) was added and this mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give the title compound (270 mg) as a colourless oil that solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:15](/[C:16](/[CH3:17])=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CC(=Cc1ccccc1)C(=O)O
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C(C)=C/c3ccccc3)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.00 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 1.80 g (11.1 mmol) of α-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.63 g (yield of Compound 133 as white needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]=[C:18]([F:20])[F:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.O.[F-:26].[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][C:18]([F:26])([F:20])[F:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C=C(F)F)cc2C1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(CC(F)(F)F)cc2C1
Temperature: 120 °C
Yield: 48 %

Procedure:
To a stirred solution of 0.71 mmol 5-(2,2-difluoro-vinyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 5 nml DMSO and 0.25 ml water was added 4.98 mmol potassium fluoride and the mixture was heated at 120° C. for 2 h. The mixture was cooled to room temperature and then taken up in THF and washed sequentially with water and with brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (48% yield). MS (m/e): 246.3 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[N:9]=1.[H-].[Na+]>O1CCCC1>[Cl:7][C:8]1[N:9]=[C:10]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[N:11]=[C:12]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])[CH:13]=1
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reaction time: 0.25 h

Procedure:
To a solution of (2R,3R)-butane-2,3-diol (250 mg) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii)) (427 mg) in anhydrous tetrahydrofuran (20 ml) at ambient temperature was added 60% sodium hydride (33.4 mg). After stirring for 15 minutes the reaction mixture was partitioned between aq. ammonium chloride solution and ethyl acetate. The organics collected, dried (MgSO4) and solvents removed under vacuo to give the subtitle compound as colourless gum. Yield: 525 mg.