Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:38])[C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])C(=O)C(F)(F)F)=[CH:15][C:14]=3[O:36][CH3:37])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:6]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:38])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[CH:15][C:14]=3[O:36][CH3:37])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:6]=2[CH:49]=1
Reactant: COc1cc(N(CCOc2ccccc2C)C(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(NCCOc2ccccc2C)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonyl-methyl]-1-[2-methoxy-4-{N-[2-(2-methylphenoxy)ethyl]-N-trifluoroacetylamino}-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.45 g) in methanol (20 ml) is added a solution of potassium carbonate (0.11 g) in water (5 ml), and the mixture is stirred at room temperature for 12 hours. The mixture is evaporated to remove the solvent, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is dried, evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=80:1→50:1→30:1), and recrystallized from acetone/n-hexane to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{2-methoxy-4-[2-(2-methylphenoxy)ethylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.12 g) as white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(N)(=[S:11])C>Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[S:11])[NH2:2]
Reactant: N#Cc1ccccn1
Reactant: CC(N)=S
Agent: Cl
Product: NC(=S)c1ccccn1
Reaction time: 1.33 h

Procedure:
Adapting the general method of Taylor, a mixture of 2-cyanopyridine (7.28 g, 7.0 mmol) and thioacetamide (10.52 g, 14.0 mmol) was treated with 60 ml of HCl-saturated DMF, and the solution was stirred vigorously in an open flask on an oil bath set initially at 80° C. (the temperature gradually rising to 95° C. over the coarse of the reaction). Taylor, E. C. et al., J. Am. Chem. Soc. 1960, 82, 2656-2657. After 80 minutes (TLC monitoring), the resulting orange suspension was cooled, neutralized with con. NaOH/ice, and extracted with EtOAc. The extract was washed with water (3×) and then concentrated to a light brown solid which was triturated with warm water and collected. The dried product was passed over a silica gel column eluting with EtOAc:hexanes (2:1) to give, after removal of most of the solvent and dilution with hexanes, a yellow crystalline solid (6.36 g, 66%), mp 136-137° C.; lit mp 137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]([O:44][C:45]([NH:47][CH:48](P(OC)(OC)=O)[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:52][O:51][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:41]([CH3:42])([CH3:40])[CH3:43])=[O:46])=[CH:23][C:21]1[CH:20]=[CH:19][C:17]2[O:18][C@@H:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)[CH2:14][O:15][C:16]=2[CH:22]=1
Reactant: O=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.7 %

Procedure:
(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6 carbaldehyde (2.1 g) was dissolved in 8 mL dry DCM under nitrogen at rt and DBU (1.61 g) was added by syringe. A solution of Boc-phosphonoglycine trimethyl ester (1.58 g) in 4 mL of dry DCM was added to the reaction mixture and stirred at rt. for 12 hours. Reaction mixture was directly loaded on to silica gel column (40% hexanes in DCM to DCM) gave 1.8 g pure product. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.46 (d, 1H), 7.32-7.38 (m, 1H), 7.18-7.28 (m, 3H), 7.10-7.15 (m, 1H), 6.94-7.06 (m, 4H), 5.13 (m, 1H), 5.03 (s, 2H), 4.36 (m, 1H), 4.01 (m, 1H), 3.84 (s, 3H), 1.44 (s, 9H). LCMS (m/z): 587.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH:8]=1)[NH2:7].BrC1C=CC=C2C=1C(O)=[N:16]N2>>[Br:1][C:2]1[CH:8]=[C:6]2[C:5]([C:9]([OH:11])=[N:16][NH:7]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: Oc1n[nH]c2cccc(Br)c12
Product: Oc1n[nH]c2cc(Br)ccc12

Procedure:
6-Bromo-1H-indazol-3-ol CCVII was prepared from 5-bromo-2-carboxyaniline (JOC, 1997, 62, 1240) using the procedure described for preparation of 4-Bromo-1H-indazol-3-ol CLXXXIII (Example 37).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.O.C([NH2:16])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:8])[NH:16][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: NC=O
Solvent: O
Product: O=C1NC(=O)c2cc(Cl)ccc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
A solution of 10.0 g of 4-chlorophthalic anhydride in 24.6 g of formamide is heated at a temperature in the region of 120° C. with stirring for 3 hours and is then cooled to a temperature in the region of 20° C. and poured into 100 cm3 of water. After stirring for 30 minutes, the mixture is filtered and the precipitate is then dried under vacuum at a temperature in the region of 60° C. 10.4 g of 4-chlorophthalimide are thus obtained in the form of a solid melting at 171° C. Rf=0.07 (thin layer chromatography on silica gel, eluent: dichloromethane).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH2:14].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH:14][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc2c(cc1Oc1ccc(F)cc1F)CCC2
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)CCC2
Reaction time: 3 h

Procedure:
At 0° C., 13.1 g of 6-(2,4-difluorophenoxy)-5-indanylamine in 60 ml of pyridine was combined with 4.0 ml of methanesulfonyl chloride. After 3 hours at 0° C. and 16 hours at 20° C., the mixture was concentrated, the residue was taken up in chloroform, the solution was washed with 1N hydrochloric acid, and concentrated. Recrystallization of the residue from ethanol yielded 8.1 g of N-[6-(2,4-difluorophenoxy)-5-indanyl]methanesulfonamide, mp 85°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[N:18][NH:19][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[I:20]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[C:17]([I:20])=[N:18][NH:19][C:13]=3[CH:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cc3[nH]ncc3cn2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)cc(-c2cc3[nH]nc(I)c3cn2)c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine (0.80 g, 3.1 mmol) and N-iodosuccinimide (0.78 g, 3.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at r.t. over weekend. Water was added to the mixture with stirring. The light brown solid precipitated and was collected by filtration to afford the desired product (0.83 g) which was directly used in next step reaction without further purification. LCMS (M+H)+=382.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:31]>N>[OH:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCOCC1
Agent: N
Product: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Yield: 78.8 %

Procedure:
A solution of 3,4-dihydro-6-methoxy-3-((pivaloyloxy)methyl)-7-(3-morpholinopropoxy)quinazolin-4-one (4.93 g, 11.4 mmol) in a saturated solution of methanolic ammonia (70 ml) was stirred at ambient temperature for 2 days. The volatiles were removed by evaporation. The solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (2.87 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:12]#[N:13].[K+]>ClCCl.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH2:4][C:12]#[N:13]
Reactant: COc1ccc(CBr)c(Cl)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC#N)c(Cl)c1
Yield: 96 %

Procedure:
212 g (purity 82%) of 2-chloro-4-methoxybenzyl bromide in 900 ml of dichloromethane are reacted in the course of 4 h at 40° C. with 176 g of potassium cyanide in 675 ml of water and 15.5 g of tetrabutylammonium hydrogen sulfate. After working-up, 157 g of brownish oil are obtained (purity 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[CH3:24][C:25]1[O:26][C:27]([CH3:33])=[C:28]([C:30](Cl)=[O:31])[N:29]=1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:28]5[N:29]=[C:25]([CH3:24])[O:26][C:27]=5[CH3:33])=[O:31])[CH:23]=[CH:22][CH:21]=4)=[CH:11][N:10]3[N:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C)o1
Yield: 70.2 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol) in N,N-dimethylacetamide (5 mL) was added with stirring under ice-cooling 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (108 mg, 0.678 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (68.6 mg, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[CH2:28][CH2:29][CH:30]([OH:33])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: NCC1(c2ccc(F)cc2)CCC(O)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(F)cc5)CCC(O)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and 4-(aminomethyl)-4-(4-fluorophenyl)cyclohexanol (amine intermediate “T”) were reacted to give the title compound. LC/MS (M+H)+: 568. Ret. time: 1.51 min. (Condition G); analytical HPLC Ret. time: 8.11 min (Condition H).
Reaction SMILES: [F:1]/[C:2](=[C:13](/[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH:20]=[C:19]2[CH:30]([CH3:32])[CH3:31])\[CH2:14][CH3:15])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.C1COCC1>[F:1]/[C:2](=[C:13](/[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[O:22][C:21]([CH3:29])([CH3:28])[CH:20]=[C:19]2[CH:30]([CH3:31])[CH3:32])\[CH2:14][CH3:15])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC/C(=C(F)/C=C/C(C)=C/C(=O)O)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 6-fluoro-7-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)3-methyl-nona-2E,4E,6E-trienoate (Compound 117, 86 mg, 0.20 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a light yellow solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([C:24]2[CH:28]=[CH:29][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=2)=[O:26])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g), 4-(chloromethyl)benzoyl chloride (756 mg), triethylamine (1.53 mL), and tetrahydrofuran (30 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (1.35 g, quant.) as crystals.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[OH:20])[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1)=[O:4].C(OCC)(=O)C.Cl>O1CCCC1.O>[OH:20][C:19]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[CH2:3][OH:4]
Reactant: COC(=O)c1ccc(O)c(-n2cccc2C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(-n2cccc2CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Sodium borohydride (0.46 g) was added to a solution of methyl 3-(2-formylpyrrol-1-yl)-4-hydroxybenzoate (3.0 g) in tetrahydrofuran (30 ml) and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was added to the mixture of ethyl acetate and water and adjusted to pH 7.5 with 6N-hydrochloric acid. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give methyl 4-hydroxy-3-(2-hydroxymethylpyrrol-1-yl)benzoate (2.54 g).
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>O1CCOCC1.CO>[NH:14]1[CH2:15][CH2:16][CH:11]([O:10][CH2:9][CH2:8][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C1CCN(CCOC2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 4 N HCl solution in dioxane (6 mL) was added to a solution of tert-butyl 4-(2-(piperidin-1-yl)ethoxy)piperidine-1-carboxylate (108) (6.5 g, 20.80 mmol) in MeOH (16 mL) and the reaction mixture was stirred at room temperature for 6 hours. Removal of solvent afforded the desired compound as its hydrochloride salt. This salt was dissolved in methanol (50 ml) and MP-carbonate (14.88 g, 33.61 mmol) was added. The resulting mixture was filtered and the solvent removed to give the desired material, as a clear liquid which was used without further purification; 1H NMR (400.132 MHz, CDCl3) δ 1.33-1.47 (2H, m), 1.50-1.71 (3H, m), 1.86-1.96 (4H, m), 2.50-2.67 (6H, m), 3.00-3.14 (4H, m), 3.34 (1H, septet), 3.55 (2H, t), 3.60 (2H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[N:10]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[OH:21])[CH2:15][CH2:14]3)[N:10]([C:28]3[N:29]=[CH:30][CH:31]=[CH:32][N:33]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCC(c2cc(-c3ccc(Cl)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CN1CCC(c2cc(-c3ccc(Cl)cc3)nn2-c2ncccn2)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of EXAMPLE 35 (50 mg, 0.109 mmol) in MeOH (1 mL) was added sodium borohydride (13 mg, 0.33 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (5% MeOH/DCM) to give the title compound. LC-MS m/z=460.17 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=4.7 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.43-7.37 (m, 5H), 7.32-7.27 (m, 3H), 6.67 (s, 1H), 4.83 (dd, J=10.2 Hz, J=3.6 Hz, 1H), 3.81-3.72 (m, 1H), 3.35 (d, J=11.4 Hz, 1H), 3.01 (d, J=11.8 Hz, 1H), 2.66-2.46 (m, 3H), 2.32-2.22 (m, 1H), 2.21-2.08 (m, 2H), 1.96-1.80 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([Br:17])=[CH:15][CH:16]=1)[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([Br:17])=[CH:15][CH:16]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(Br)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccc(Br)nc1)C(=O)O
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
(S)-tert-Butyl 2-amino-3-(6-bromopyridin-3-yl)propanoate (4 g) was dissolved in DCM (20 mL) and the solution obtained was treated with TFA (20 mL). The mixture was stirred for 0.5 h, concentrated in vacuo, azeotroping with toluene, and loaded onto an NH2-silica cartridge. Non acidic impurities were eluted with acetonitrile, then the desired product was eluted with 10% acetic acid in acetonitrile. Solvent was removed in vacuo to give the sub-title compound (2.5 g).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[CH:7][C:6](CC2C=C3C(=C4C=CC=CC=24)N=CN([C@H]2CCOC[C@@H]2O)C3=O)=CC=1.[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36](Cl)[CH:35]=1>>[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[N:8]([CH2:3][CH3:2])[CH:7]=[CH:6][C:35]=12
Reactant: O=c1c2cc(Cc3ccc(CO)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: Clc1cc(CBr)ccn1
Product: CCn1ccc2c(CBr)ccnc21

Procedure:
The title compound was prepared by the procedure described for the synthesis of 6-[(2-chloropyridin-4-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3R)-one in Example 15, substituting 4-(bromomethyl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine for 4-(bromomethyl)-2-chloropyridine. The resultant orange solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 455.2087 for [M+H]+ [Calc'd for C27H27N4O3, [M+H]+=455.2078]: 1H NMR (400 MHz, d6-DMSO) δ 9.01-8.98 (m, 1H), 8.71 (s, 1H), 8.14-8.08 (m, 2H), 8.01 (s, 1H), 7.75-7.71 (m, 2H), 7.56 (s, 1H), 6.74-6.72 (m, 1H), 6.59 (s, 1H), 5.31 (d, J=5.5 Hz, 1H), 4.80 (s, 2H), 4.63 (br s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.18-4.15 (m, 1H), 3.99-3.92 (m, 1H), 3.42 (t, J=11.1 Hz, 1H), 3.14 (t, J=10.4 Hz, 1H), 2.26 (br s, 1H), 1.91-1.89 (m, 1H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH:22][NH2:23].O>CCOCC.C(N(CC)CC)C.C(Cl)Cl>[C:1]([CH2:3][C:4]([N:22]([C:15]1[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])[NH2:23])=[O:6])#[N:2]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: N#CCC(=O)N(N)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanoacetic acid (8.5 g, 0.10 mol) in 200 mL of dry ether was treated with 20.8 g (0.10 mol) of phosphorous pentachloride, warmed briefly to reflux and let cool to room temperature at which time all of the phosphorous pentachloride, had dissolved. After a small amount of insoluble material was removed by filtration, the ether was removed on the rotary evaporator. Then 100 mL of toluene was added and stripped to remove phosphorous oxytrichloride. The residual pale yellow oil was immediately dissolved in 50 mL of cold methylene dichloride and added to a cold suspension of 21.15 g (0.10 mol) of 2,4,6-trichlorophenylhydrazine in 14.0 mL of triethylamine and 100 mL of methylene dichloride, keeping the temperature below 20° C. by use of an ice bath. The reaction mixture was allowed to warm to room temperature and stirred for one hour. Then 500 mL of cold water was added. The precipitated solid was filtered and washed with water and with a little methylene dichloride to give the intermediate 2-cyano-N-(2,4,6-trichlorophenyl)acethydrazide, 14.92 g (54%), m.p. 166-168° C. Anal. Calcd. for C9H6ON3 : C, 38.81; H, 2.17; N, 15.09. Found: C, 38.83; H, 2.06; N, 14.81.
Reaction SMILES: C1([C:4]2[CH:24]=[CH:23][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15](F)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[CH:6][CH:5]=2)CC1.[CH3:25][C:26]1([CH3:37])[O:30]C2C=CC(C=O)=CC=2[O:27]1.FC(F)(F)C1C=C(CCN)C=CC=1.[BH4-].[Na+]>>[CH3:25][C:26]1([CH3:37])[O:30][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:13]=3)=[CH:23][C:24]=2[O:27]1
Reactant: CC1(C)Oc2ccc(C=O)cc2O1
Reactant: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: NCCc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)Oc2ccc(CNCCc3cccc(C(F)(F)F)c3)cc2O1

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 84 mg of 2,2-dimethyl-benzo[1,3]dioxole-5-carbaldehyde (0.47 mmol), 89 mg of 2-(3-trifluoromethylphenyl)-ethylamine (0.47 mmol) and 27 mg of sodium borohydride (0.71 mmol). The isolated colorless semisolid (137 mg, 83%) was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.66 (s, 6H), 2.89 (m, 4H), 3.70 (s, 2H), 6.68 (m, 3H), 7.39 (m, 2H), 7.46 (m, 2H).