Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:29]1[O:39][C:38]2[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][C:31]=2[O:30]1>>[O:39]1[C:38]2[CH:37]=[CH:36][C:33]([CH2:34][N:19]3[C:14]4[C:15](=[O:18])[N:16]([CH3:17])[C:11]([CH:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:7]([OH:9])=[O:8])=[C:12]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)[C:13]=4[CH:21]=[CH:20]3)=[CH:32][C:31]=2[O:30][CH2:29]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc3c(c2)OCO3)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 27 step D from methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 3,4-methylenedioxybenzyl chloride (50% in dcm), and was isolated as beige solid after reverse phase chromatography (41%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9H), 2.42 (s, 3H), 3.67 (s, 3H), 5.46 (s, 1H), 5.63-5.81 (m, 2H), 5.92 (s, 2H), 6.01 (d, J=2.9 Hz, 1H), 6.70-6.84 (m, 3H), 7.00 (d, J=2.8 Hz, 1H), 7.27-7.30 (m, 2H), 7.30-7.38 (m, 1H), 7.46-7.58 (m, 1H). LCMS (m/z) ES+=503 (M+1).
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccccc1
Reactant: CC(C)O
Product: CC(C)c1ccccc1

Procedure:
A similar process is described in EP 0371738 wherein the iso-propanol obtained from the hydrogenation step is directly used as alkylation agent in the alkylation of benzene to obtain cumene. The hydrogenation of acetone described in that reference is also similar using Raney nickel in presence of water whereby acetone conversion is only 99% and the Iso-propanol yield is 98.7%.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([OH:23])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, light yellow solid, m.p. 160-162° C. and MS: m/e=334 (M+Na+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and tert.-butyl alcohol.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(OC)cc3)CC2)n(C(C)(C)C)n1

Procedure:
162 mg (83%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(4-methoxyphenyl)piperazine (87 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[S:42]([N:45]([CH2:49][CH2:50][O:51][CH2:52][C:53](O)=[O:54])[CH:46]1[CH2:48][CH2:47]1)(=[O:44])=[O:43].[F:56][C:57]1[CH:58]=[C:59]([C:63]2([O:69][CH2:70][CH2:71][N:72]3[CH2:76][CH2:75][CH2:74][CH2:73]3)[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)[CH:60]=[CH:61][CH:62]=1>O1CCCC1>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:36]=1[S:42]([N:45]([CH:46]1[CH2:48][CH2:47]1)[CH2:49][CH2:50][O:51][CH2:52][C:53]([N:66]1[CH2:65][CH2:64][C:63]([C:59]2[CH:60]=[CH:61][CH:62]=[C:57]([F:56])[CH:58]=2)([O:69][CH2:70][CH2:71][N:72]2[CH2:76][CH2:75][CH2:74][CH2:73]2)[CH2:68][CH2:67]1)=[O:54])(=[O:44])=[O:43]
Reactant: Fc1cccc(C2(OCCN3CCCC3)CCNCC2)c1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(OCCN2CCCC2)(c2cccc(F)c2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
DIPEA (2 eq.) and HATU (1.2 eq.) were added to a solution of tetrahydrofuran and 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetic acid [acid K] (1 eq.) at 0° C. 4-(3-Fluorophenyl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidine [amine C] (1.2 eq.) was taken up in tetrahydrofuran (2 ml/mmol) and the solution was rendered basic with DIPEA (2 eq.) and added to the reaction mixture at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The mixture was concentrated to dryness on a rotary evaporator, the residue was taken up in methylene chloride and the mixture was washed with water and sat. sodium chloride solution and dried over sodium sulfate. The organic phase was concentrated and the crude product was purified by means of column chromatography (5% methanol in methylene chloride). Yield: 60%. MS, Rt=3.6 min, m/z=622.4 [MH]+
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(Br)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1c(Br)cnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
5-Bromo-4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (4.1 g, 10.57 mmol, see Example 1) was placed in THF (80 mL) at room temperature. TBAF (1.1 equivalents) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then poured into water and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give a crude solid. The solid was then suspended in 10:1 hexanes:DCM, and filtered to give the solid product 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (2.20 g, 89.9% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]1=[O:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:8][C:4]1[C:3](=[O:9])[N:2]([CH3:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccn(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1cccc(CBr)c1=O
Yield: 32.6 %

Procedure:
1,3-Dimethylpyridin-2(1H)-one (0.54 g, 4.4 mmol) was added to CCl4 (100 mL). N-Bromosuccinimide (0.78 g, 4.4 mmol) and benzoyl peroxide (0.11 g, 0.44 mmol) were added and the reaction mixture was refluxed for 3 hours. The reaction was cooled, filtered and concentrated. The residue was suspended in Et2O (10 mL) and filtered to provide 3-(bromomethyl)-1-methylpyridin-2(1H)-one (0.29 g, 32% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[Cl:11][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]=12
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc(Cl)c2ccnc-2[nH]1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2ccnc-2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.7 %

Procedure:
To a stirring solution of 2-amino-4-chloro-pyrrolo[2,3-d]pyrimidine (7.3 g, 43.61 mmol) in anhydrous pyridine (120 mL) was added pivaloyl chloride (18.7 mL, 152.63 mmol). The reaction was stirred at RT under nitrogen for 16 h and quenched with MeOH (50 mL). The solvents were then removed in vacuo, and the residue was co-evaporated with toluene (100 mL). The resulting residue was dissolved in EtOAc (150 mL) and washed with 0.1 M HCl (3×75 mL). The organic layer was dried (MgSO4) and evaporated. The crude material was resolved by silica chromatography (30% EtOAc/hexane) to yield 9a (12.2 g) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:10][CH2:11][C:12]([NH:14][CH:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:16])=[O:13].O>O1CCCC1.C(OCC)(=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH3:16])=[CH:22][CH:21]=1
Reactant: Cc1ncc[nH]1
Reactant: CC(NC(=O)CCCl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nccn1CCC(=O)NC(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methylimidazole (2.64 g) in dry tetrahydrofuran (THF) (40 ml ) was added over 1 minute to a stirred suspension of sodium hydride (1.54 g; 60% dispersion in oil) in THF (65 ml) under dry nitrogen. The mixture was stirred at ambient temperature for 1 hour, then heated to boiling under reflux and allowed to cool. A solution of 3-chloro-N-[1-(4-chlorophenyl)ethyl]-propionamide (5.7 g) in THF (25 ml) was added and the mixture stirred under reflux for 16 hours. The mixture was cooled and water (100 ml) was added portion-wise with stirring followed by ethyl acetate (200 ml). The acidic layer was separated and extracted with ethyl acetate and the combined ethyl acetate extracts extracted with hydrochloric acid (5M). The combined acidic extracts were basified with concentrated sodium hydroxide solution and extracted with ethyl acetate to give an oil. The oil was triturated with ether and filtered to give N-[1-(4-chlorophenyl)ethyl]-3-(2-methylimidazol-1-yl)propionamide, m.p. 135°-137° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([CH:13]([CH2:16][CH3:17])[CH2:14]O)[CH3:12]>C([O-])(=O)C([O-])=O.[Sn+4].C([O-])(=O)C([O-])=O.O>[C:1]([O:10][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCC(CC)CO
Reactant: CCCCCCCC(=O)O
Agent: O=C([O-])C(=O)[O-]
Agent: [Sn+4]
Solvent: O
Product: CCCCCCCC(=O)OCC(CC)CC
Temperature: 10 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
187.2 g (1.3 mol) of caprylic acid, 214.0 g (2.09 mol) of 2-ethylbutanol and 0.14 g of tin oxalate (“Fascat 2001”) were heated to 160° C. under N2, during which water separation was observed. Once water separation had subsided, the mixture was heated to 210° C. in 10° C. steps. This temperature was then held for 3 h. Then, firstly the excess alcohol was removed by distillation and then the product was distilled at 8-12 mbar and 136-141° C. The product (225.6 g) was obtained as a clear liquid with an acid number of 0.47 and an OH number of 1.36.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([O:19][CH2:20][CH:21]([O:42][CH2:43][N:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46][C:45]1=[O:51])[CH2:22][O:23][C:24](=[O:41])[C@H:25]([C@H:37]([CH2:39][CH3:40])[CH3:38])[NH:26]C(OCC1C=CC=CC=1)=O)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=O)C1C=CC=CC=1.C1CC=CCC=1.O>[Pd].C(O)(=O)C>[NH2:11][C@H:12]([C:17]([O:19][CH2:20][CH:21]([O:42][CH2:43][N:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46][C:45]1=[O:51])[CH2:22][O:23][C:24](=[O:41])[C@H:25]([C@H:37]([CH2:39][CH3:40])[CH3:38])[NH2:26])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC)OCn1ccc(N)nc1=O
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](C)[C@H](N)C(=O)OCC(COC(=O)[C@@H](N)[C@@H](C)CC)OCn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cool mixture of 2.54 g of 2-((4-amino-1,2-dihydro-2-oxo-1-pyrimidinyl)methoxy)-1,3-propanediyl bis(N-((benzyloxy)carbonyl)-L-isoleucinate) and 5.16 g of 10% palladium catalyst in acetic acid was slowly added 6.4 mL of 1,4-cyclohexadiene. The mixture was allowed to stir at room temperature for 3 h. The reaction mixture was filtered through a pad of Celite, the filtrate was then concentrated and dried in the lyophiliser for 3 d. The residue was scraped off, affording 2.079 g (82%, as the acetic acid salt) of a beige foam. The elemental analysis (showing 2M of acetic acid and 1M of water), UV, 1H. 13C-NMR spectra were consistent with the title structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])(=O)C.[C:28](OCC)(=[O:30])[CH3:29].CCCCCC>>[C:28]([N:4]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[CH3:1])(=[O:30])[CH3:29]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)C2CCCCC2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCCCCC
Product: CC(=O)N(C)c1c(C(=O)C2CCCCC2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared from 3-acetylamino-6-chloro-2-cyclohexylcarbonyl-1-(ethoxycarbonyl)indole (step 1) according to the procedure described in Example 146. m.p.: 162-163° C. (ethyl acetate/hexane)
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=O)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH2:31][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CN4CCOCC4)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (300 mg) in tetrahydrofuran (20 mL) were added morpholine (83 mg), sodium triacetoxyborohydride (270 mg) and triethylamine (177 μL) and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (141 mg, yield 41%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 543 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C([O-])([O-])=O.[Na+].[Na+]>>[OH:1][CH:2]1[CH2:6][N:5]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:21])([F:20])[F:10])[CH:13]=2)[CH:4]([C:7]([O:9][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)=[O:8])[CH2:3]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(OCc1cccc(C(F)(F)F)c1)C1CC(O)CN1Cc1cccc(C(F)(F)F)c1

Procedure:
The title compound (D81) (1.02 g) was prepared according to the general procedure for substituted benzyl amines preparation starting from cis-4-Hydroxy-D-proline (4.0 g; available from Aldrich#H5877) and 3-(Trifluoromethyl)benzyl bromide (9.37 ml). (Na2CO3: 2.5 eq; Reaction time: 24 hrs; 60° C.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[CH2:7][O:8]2)=[CH:4][CH:3]=1.O.NN>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][O:8][C:9]=2[CH:10]=1
Reactant: O=C1COc2cc(O)ccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: Oc1ccc2c(c1)OCC2
Reaction time: 1.5 h

Procedure:
6-Hydroxycoumaran-3-one (15 g) was suspended in ethanol (75 ml) and hydrazine hydrate (10 ml, 90%) was added and the mixture heated at reflux for 1 hour. The solvent was evaporated and a solution of potassium hydroxide (15 g) in ethylene glycol (100 ml) was added to the residue. The resulting mixture was distilled with stirring until the internal temperature reached 185°-190° C. This temperature was maintained until no more nitrogen was evolved, approximately 1.5 hours. After cooling, the mixture was added to dilute hydrochloric acid containing sufficient acid to make the mixture acidic. This acidified mixture was then extracted with ether, dried and distilled (110°-120° C./0.75 mm) to give 6-hydroxy-2,3-dihydrobenzofuran.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28](O)[CH:29]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:26]1[CH:25]=[C:24]([F:23])[CH:29]=[CH:28][C:27]=1[N+:31]([O-:33])=[O:32])[CH3:2]
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethanol (4.2 ml) in tetrahydrofuran (65 ml) was added a solution of triphenylphosphine (13 g) and 5-fluoro-2-nitrophenol (10 g) in tetrahydrofuran (65 ml). To this solution was added diethyl azodicarboxylate (10 ml) under ice-cooling and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure and diisopropyl ether was added. The precipitated crystals were collected by filtration and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=4:1) to give a yellow oil. To this oil was added ethyl acetate, washed with an aqueous sodium hydroxide solution, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (9.6 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:28][C:18]4[CH:19](CNC(=O)C)[NH:20][CH2:21][CH2:22][C:17]=4[C:15]=3[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.FC1C=C(S(C2C=CC3OC=C([CH2:47][CH2:48][NH:49][C:50](=[O:56])OC(C)(C)C)C=3C=2)(=O)=O)C=CC=1.O1CCO[CH:59]1NCC.C(N)(=O)C.O1CCOC1CCN.C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:28][C:18]4[CH:19]([CH2:47][CH2:48][NH:49][C:50](=[O:56])[CH3:59])[NH:20][CH2:21][CH2:22][C:17]=4[C:15]=3[CH:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCNC1OCCO1
Reactant: CC(C)(C)OC(=O)NCCc1coc2ccc(S(=O)(=O)c3cccc(F)c3)cc12
Reactant: CC(=O)NCC1NCCc2c1oc1ccc(S(=O)(=O)c3cccc(F)c3)cc21
Agent: CC(N)=O
Agent: NCCC1OCCO1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCCC1NCCc2c1oc1ccc(S(=O)(=O)c3cccc(F)c3)cc21

Procedure:
Prepared as described for N-({6-[(3-fluorophenyl)sulfonyl]-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridin-1-yl}methyl)acetamide using tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate and N-[1,3]dioxolan-2-yl-ethylamine)-acetamide, which was prepared from 2-[1,3]dioxolan-2-yl-ethylamine and acetic anhydride. MS m/z 417 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH2:12][CH2:13][CH2:14][N:15]=1.O.[OH-].[Na+]>CO.C(O)(=O)C>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: Fc1ccc(C2=NCCC2)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(C2CCCN2)c(Br)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
Add sodium tetrahydroborate (146 mg, 3.7 mmol) to a solution of 5-(2-bromo-4-fluorophenyl)-3,4-dihydro-2H-pyrrole (420 mg, 1.73 mmol) in methanol-acetic acid (saturated; 10 mL) mixture at −40° C. After warming up to RT, add water (10 mL) and make the solution basic with a NaOH solution (2 N). Extract the solution with DCM, wash the organic solution with aqueous saturated sodium chloride, dry over potassium carbonate, and remove the organic solvent to give the title compound (300 mg, 71%). MS (ES) m/z 236 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(Cl)ncnc2c1
Reactant: Clc1ccc2c(c1)NCC2
Product: Cc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Yield: 14 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 14% yield from 6-chloro-indoline and 4-chloro-7-methyl-quinazoline. (M.P. 265° C.; LC-MS: 296 (MH+)).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([N:11]([CH:13]2[CH2:15][CH2:14]2)C)[N:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:28](N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[N:3]=[C:4]([NH:11][CH2:13][CH:15]2[CH2:14][CH2:28]2)[N:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(c1nc(Cl)c(C#N)c(Cl)n1)C1CC1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCC2CC2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(cyclopropyl-methyl-amino)-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in the presence of N-ethyl-diisopropylamine in dioxane at room temperature during 18 hours to yield 4-chloro-2-(cyclopropylmethyl-amino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=369.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:14]([Cl:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH:19]([OH:25])[CH2:18]2>C(Cl)Cl>[ClH:16].[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:14]([O:25][CH:19]3[CH:20]4[CH2:23][CH2:24][N:17]([CH2:22][CH2:21]4)[CH2:18]3)=[O:15])[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C1(c2cccc([N+](=O)[O-])c2)CCC1
Reactant: OC1CN2CCC1CC2
Solvent: ClCCl
Product: Cl
Product: O=C(OC1CN2CCC1CC2)C1(c2cccc([N+](=O)[O-])c2)CCC1

Procedure:
The title compound was prepared in an analogous manner to that in Example 36. 1-(3-Nitrophenyl)cyclobutanecarbonyl chloride, prepared from the compound prepared in Example 33, was reacted with 3-quinuclidinol in CH2Cl2 for 2 h. The crude was chromatographed on silica gel using EtOAc-Et3N 90:10 as eluent. The yield was 0.4 g (26%); mp 191-192° C.; 1H NMR (CD3OD) δ 1.73-2.29 (m, 7H), 2.62 (m, 2H), 2.94 (m, 2H), 3.02-3.36 (m, 5H), 3.65-3.75 (m, 1H), 5.10 (m, 1H), 7.60-7.66 (m, 1H), 7.74-7.78 (m, 1H), 8.13-8.18 (m, 2H). Anal. (C18H22N2O4.HCl) C, H, N.