Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:7]([C:13]1[CH:35]=[CH:34][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:28]5=[N:29][CH:30]=[N:31][C:32]([NH2:33])=[C:27]5[CH:26]=[N:25]4)[CH2:20][CH2:19]3)=[CH:15][CH:14]=1)=[N:8]2.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[NH2:33][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:24]([CH:21]3[CH2:20][CH2:19][N:18]([CH2:17][C:16]4[CH:34]=[CH:35][C:13]([C:7]5[C:6]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)=[CH:5][C:4]6[C:3](=[O:2])[NH:12][CH:11]=[CH:10][C:9]=6[N:8]=5)=[CH:14][CH:15]=4)[CH2:23][CH2:22]3)[N:25]=[CH:26][C:27]=12
Reactant: COc1nccc2nc(-c3ccc(CN4CCC(n5ncc6c(N)ncnc65)CC4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Nc1ncnc2c1cnn2C1CCN(Cc2ccc(-c3nc4cc[nH]c(=O)c4cc3-c3ccccc3)cc2)CC1
Temperature: 150 °C

Procedure:
A mixture of 1-{1-[4-(5-methoxy-3-phenyl-1,6-naphthyridin-2-yl)benzyl]-piperidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.092 mmol) and pyridine hydrochloride 9500 mg, 4.35 mmol) was heated at 150° C. for 10 minutes. The cooled mixture was diluted with water and made neutral with sodium bicarbonate solution. The white solid was collected by filtration, dried, and then digested in acetonitrile with a little methanol. Upon cooling the pure product was isolated by filtration. 1H-NMR (500 MHz, DMSO-d6): δ 11.60 (1H, br s), 8.38 (1H, s), 8.15 (1H, s), 8.07 (1H, s), 7.50 (1H, d, J=7.3 Hz), 7.31-7.60 (5H, m), 7.24-7.28 (4H, m), 6.69 (1H, d, J=7.3 Hz), 4.57 (1H, m), 3.53 (2H, s), 2.91 (2H, m), 2.11-2.17 (4H, m), 1.80-1.87 (2H, m). m/e (m+1): 529.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[CH2:10][C:5]2=[CH:4][CH:3]=1.[C:12]([O:15][CH:16](OCC)OCC)(=O)[CH3:13]>>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[C:10](=[CH:16][O:15][CH2:12][CH3:13])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)nc2N1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC=C1C(=O)Nc2nc(Cl)ccc21

Procedure:
This compound was synthesized from 6-chloro-1H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ11.06 (s, 1H); 7.84 (s, 1H); 7.63 (d, 1H); 6.98 (d, 1H); 4.39 (m, 2H); 1.32 (m, 3H).
Reaction SMILES: C([Li])CCC.[CH3:6][NH:7][S:8]([C:11]1[C:12]([CH3:21])=[CH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1)(=[O:10])=[O:9].[C:22](=[O:24])=[O:23].Cl>CCCCCC.O1CCCC1.O.CCOCC>[CH3:6][NH:7][S:8]([C:11]1[C:12]([CH2:21][C:22]([OH:24])=[O:23])=[CH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1)(=[O:9])=[O:10]
Reactant: O=C=O
Reactant: CNS(=O)(=O)c1cc2c(cc1C)CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CNS(=O)(=O)c1cc2c(cc1CC(=O)O)CCCC2

Procedure:
100 mL of a 1.5 molare (150 mmol) butyl lithium in hexane were added to a solution of 18 g (75 mmol) 2-methyl-5,6,7,8-tetrahydro-naphthalene-3-sulfonic acid methylamide in 200 mL tetrahydrofuran at −20° C. The resulting mixture was allowed to come to room temperature and was poured onto a mixture of ether and solid CO2. After addition of water the resulting mixture was acidified with dilute HCl and then extracted with CH2Cl2. The CH2Cl2 solution was washed, dried and concentrated. Recrystallization from ether/petroleum ether gave 15.8 g 3-(N-methyl-sulfamoyl)-5,6,7,8-tetrahydro-naphthalene-2-acetic acid (melting point: 153-155° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C([O-])(C)(C)C.[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].CCOC(C)=O.CCCCCCC>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:4]2[CH:3]=[C:2]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:7]=[C:6]([Br:8])[CH:5]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(COc2cc(Br)cc(Br)c2)cc1
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCCC
Product: COc1ccc(COc2cc(Br)cc(Nc3cccnc3)c2)cc1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
An oven-dried flask was charged with (±)-BINAP (504 mg, 0.81 mmol), Pd2(dba)3 CHCl3-complex (278 mg, 0.27 mmol) and then flushed with argon. Degassed toluene (50 mL) was added and the solution was stirred for 10 min. A second oven-dried flask was charged with 3,5-dibromo-1-p-methoxy-benzyloxybenzene (20.0 g, 53.8 mmol), 3-aminopyridine (2.72 g, 26.9 mmol) and sodium tert-butanolate (3.61 g, 37.6 mmol) in degassed toluene (100 mL) and the mixture was heated to 90° C. The catalyst solution was then added to the mixture and the reaction mixture was stirred at 90° C. for 40 h. The reaction mixture was cooled to room temperature and brine (120 mL) and AcOEt (120 mL) were added and the mixture was filtered over Hyflo. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with AcOEt (2×100 mL) and the layers were separated. The organic layer was washed with brine (2×80 mL), dried (Na2SO4) and concentrated to give the crude product. FC (SiO2, AcOEt/heptane 1:2→2:1) gave 7.96 (75%) of (3-p-methoxybenzyloxy-5-bromo-phenyl)-pyridin-3-yl-amine as yellow oil. 3,5-Dibromo-1-p-methoxy-benzyloxybenzene was recovered, repurified and can be reused.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(C)cc3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
140 (70 mg, 0.237 mmol) is dissolved in 5 ml of methanol and treated with a solution of LiOH (11.4 mg, 0.474 mmol) in 3 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.CO>O1CCCC1>[OH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCO)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Yield: 58.6 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-amide (346) (290 mg, 0.48 mmol) in tetrahydrofuran (15.0 mL) was added 1N HCl (3.0 mL) at room temperature and the reaction mixture was stirred for 1 h at the same temperature (silica TLC, 5% methanol in dichloromethane/SiO2/UV, Rf=0.5). The tetrahydrofuran was removed in vacuum and the solid obtained was filtered through a sintered funnel, washed with water and ether and dried in vacuum to get pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-amide (347) (140 mg, 59%) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])C.C(OC(=O)[C:31]1[CH:36]=[CH:35]C(I)=[CH:33][CH:32]=1)C>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:4][C:5]1([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:7][CH2:6]1)[C:3]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg, 0.24 mmol) and ethyl-4-iodo benzoate (Reagent A, 72.0 mg, 0.26 mmol) in triethylamine (4 mL) was treated with copper(I)iodide (17.0 mg, 0.09 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (61 mg, 0.09 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 85.0 mg (91%) of the title compound as an orange oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1>O>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]2[N:10]=[C:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[O:13][N:12]=2)[CH:15]=1
Reactant: COc1cccc(-c2nc(-c3cccnc3)no2)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
3-[5-(3-Methoxyphenyl)-[1,2,4]oxadiazol-3-yl)pyridine (4.0 g, 15.79 mM) and pyridine hydrochloride (37.6 g, 325 mM) were melted together at about 160° C. under an atmosphere of nitrogen for about 30 hours. This mixture was poured into H2O and stirred. The precipitated product was filtered and dried, 2.9 g, mp. >200° C.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[C:15]([C:18]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][C:22](=[O:36])[NH:23]2)(=[O:17])[CH3:16]>O1CCOCC1>[C:15]([C:18]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22](=[O:36])[NH:23]2)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2c1CCC(=O)N2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DDQ (15.0 g, 66.08 mmol) is added to a suspension of 5-acetyl-7-benzyloxy-3,4-dihydro-1H-quinolin-2-one (13.0 g, 44.02 mmol) in dioxane (130 mL) and the mixture is refluxed for 30 minutes. The reaction mixture is cooled to ambient temperature and stirred for a further 2 hours. The precipitate formed is filtered off, washed with dioxane (2×20 mL) and dissolved in dichloromethane/methanol (9:1, 600 mL). The organic phase is washed with sodium bicarbonate solution (2×100 mL), dried with sodium sulfate, and evaporated down. The residue is stirred with methanol, the precipitate formed is filtered off and dried. Yield: 8.3 g (64%); mass spectroscopy: [M+H]+=294.
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].Cl.[C:22]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:30]([CH2:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:31])[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1C(=O)N(CCC(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (1.25 g, 4.50 mmol) in dichloromethane (25 mL) was added at room temperature dropewise to a suspension of 3-amino-propionic acid tert-butyl ester hydrochloride (0.86 g, 4.70 mmol), triethylamine (0.66 ml, 4.70 mmol), acetic acid (0.51, 9.00 mmol), and sodium triacetoxyborohydride (1.09 g, 5.10 mmol) in dichloromethane (12.5 mL) and stirred over night. The reaction was extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield after evaporation of the solvent 1.21 g (58%) of the titled compound as light yellow oil. MS: 377.3 (MH+)
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[NH:12][C:11]3[C:13]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=4)=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:10]=3[N:9]=2)[CH2:3]1.[Br:30][C:31]1[C:32](Cl)=[N:33][CH:34]=[CH:35][CH:36]=1>>[Br:30][C:31]1[C:32]([N:7]2[CH2:6][CH2:5][N:4]([C:8]3[NH:12][C:11]4[C:13]([C:21]5[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=5)=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:16][C:10]=4[N:9]=3)[CH2:3][C@@H:2]2[CH3:1])=[N:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@H]1CN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CCN1
Reactant: Clc1ncccc1Br
Product: C[C@H]1CN(c2nc3cc(C(F)(F)F)cc(-c4cc(F)c(F)c(F)c4)c3[nH]2)CCN1c1ncccc1Br

Procedure:
The piperazine from step (a) above (41 mg, 0.1 mmol) reacted with 3-bromo-2-chloropyridine (19 mg, 0.1 mmol, Aldrich) under the conditions of Example 48b to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:14]([NH2:20])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(Cl)Cl.[CH3:31][CH2:32]O>>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]4[C:14](=[CH:15][C:16]=32)[N:20]=[C:31]([CH3:32])[N:21]4[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CNc1cc2c(cc1N)C1CC2CN(C(=O)OC(C)(C)C)C1
Reactant: CCO
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2cc3c(cc2n1CC(C)C)C1CC3CN(C(=O)OC(C)(C)C)C1

Procedure:
4-Amino-5-isobutylamino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (250 mg, 0.74 mmol) from Example 19B was dissolved in EtOH (10 mL) and HOAC (3 mL) and treated with 1-ethoxyethylenemalononitrile (118 mg, 0.87 mmol). The reaction proceeded as in Example 18C (18 h) and was worked up similarly to provide product (TLC 3% MeOH/CH2Cl2 (NH3) Rf0.57).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([O:23]COC)=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH3:28])[C:4]1=[O:5])[CH3:2].Cl.[OH-].[Na+].O>O1CCCC1>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH3:28])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCOC)cc3)n2C)n(CC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Yield: 97.5 %

Procedure:
Compound 145 (2.70 g, 7.02 mmol) obtained in Reference Example 88 was dissolved in 50 ml of tetrahydrofuran. To the solution was added 17.6 ml of 2N hydrochloric acid, and the mixture was heated under reflux for 2.5 hours. The reaction solution was neutralized with a 2N aqueous solution of sodium hydroxide under ice cooling, water was added thereto, and the deposited crystals were collected by filtration. The obtained crude crystals were recrystallized from 2-propanol to give 2.33 g (yield 98%) of Compound 175 as yellow grains.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OCCC2O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1CCOC12CCNCC2
Reaction time: 2 h

Procedure:
tert-Butyl 4-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iii) above; 300 mg) was dissolved in dichloromethane and trifluoroacetic acid (2 mL) was added. The solution was stirred for 2 h and was concentrated in vacuo to afford the product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([Br:12])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].[CH2:14]([O:16][C:17](OCC)([O:23]CC)[C:18](OCC)=O)[CH3:15]>CCCCCC>[Br:12][C:7]1[C:6]([CH3:13])=[C:3]([C:4]#[N:5])[C:2]2[N:1]=[C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:23])[O:10][C:9]=2[C:8]=1[F:11]
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Solvent: CCCCCC
Product: CCOC(=O)c1nc2c(C#N)c(C)c(Br)c(F)c2o1
Temperature: 130 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
Under nitrogen atmosphere, a mixture of 2-amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (6.67 g, 27.2 mmol) and ethyl triethoxyacetate (24.0 g, 54.4 mmol) was stirred at 130° C. for 15 hours. After cooling, n-hexane was added to the reaction liquid, and the precipitated solid was collected by filtration. The obtained solid was suspended and washed in diethyl ether to obtain the entitled compound (7.10 g, 80%) as a pale dark brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(=O)CC.C(Cl)Cl>[C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: c1ccc(CCCCOc2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of 5-hydroxyindole (0.5 g, 3.8 mmol), anhydrous K2CO3 (1.58 g, 11.4 mmol), (4-bromobutyl) benzene (2.11 g, 11.4 mmol), and a catalytic amount of Kl in 2-butanone (40 ml) was heated at reflux overnight under nitrogen. After allowing to cool to room temperature, the reaction mixture was filtered, the flitrate then concentrated under reduced pressure to give an oil. The oil was taken up in CH2Cl2 (50 ml) and washed successively with 2N-NaOH (1×20 ml) and water (1×20 ml). The organic portion was dried (MgSO4) and the solvent was removed under reduced pressure to give an oil. The oil was purified by column chromatography using a solvent system of CH2Cl2 /Hexane (40:60) to give 5-(4-phenylbutyloxy)indole as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[Cl:17][C:18]1[CH:19]=[C:20]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[S:6]2(=[O:16])=[O:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)c(Cl)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (522 mg) was coupled to 3-chloro-4-fluorophenylboronic acid to provide 1-(3-chloro-4-fluorophenyl)-3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (138 mg):
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]([Cl:10])(Cl)=[O:8].C(Cl)(=O)N>ClC(Cl)C>[CH3:1][NH:2][C:3]([N:5]([CH3:6])[C:7]([Cl:10])=[O:8])=[O:4]
Reactant: CNC(=O)NC
Reactant: O=C(Cl)Cl
Agent: NC(=O)Cl
Solvent: CC(Cl)Cl
Product: CNC(=O)N(C)C(=O)Cl
Temperature: 80 °C

Procedure:
To a cold suspension of 22 g. (0.25 m.) of sym-dimethylurea in dichloroethane was added dropwise with stirring a cold solution of 30 g. (0.3 m.) of phosgene in 90 ml. of dichloroethane. After the addition of the phosgene solution was complete, the reaction mixture was allowed to stir at room temperature for one hour and was then heated to 80° C. and purged with nitrogen for one hour. The reaction mixture was evaporated under reduced pressure and the residual gum was extracted twice with 350 ml. portions of either. The extracts were combined and evaporated to provide 25 g. of the carbamoyl chloride.
Reaction SMILES: C([NH:11][CH:12]([CH3:24])[CH2:13][O:14][CH:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]([CH3:19])([CH3:18])[CH3:17])(OCC1C=CC=CC=1)=O>CO.[Pd]>[NH2:11][CH:12]([CH3:24])[CH2:13][O:14][CH:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(COC(C(C)(C)C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(N)COC(C(C)(C)C)C(C)(C)C

Procedure:
N-Cbz-2-Amino 1-[di-(t-butyl)methoxy]propane is dissolved in CH3OH and hydrogenated over 5% Pd/C in a Paar hydrogenation apparatus. When the reaction is complete the mixture is filtered through Celite and concentrated to yield 2-amino 1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@H:5]1[CH2:8][C@H:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:6]1)[CH3:3].N1CC[CH2:34][CH2:33]1>>[O:25]([C:22]1[CH:21]=[CH:20][C:19]([C:11]2[N:10]=[C:9]([CH:7]3[CH2:6][CH:5]([CH2:4][N:2]4[CH2:1][CH2:34][CH2:33][CH2:3]4)[CH2:8]3)[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=23)=[CH:24][CH:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)C[C@H]1C[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Reactant: C1CCNC1
Product: Nc1nccn2c(C3CC(CN4CCCC4)C3)nc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
Prepared according to the procedure described above for trans-3-(3-dimethylaminomethyl-cyclobutyl)-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine, except using pyrrolidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][C:17]2=O)=[CH:13][CH:12]=1)[CH2:8][CH3:9].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:7]([O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][CH2:16][CH:17]2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1)[CH2:8][CH3:9]
Reactant: C1CNCCN1
Reactant: CCCOc1ccc2c(c1)C(=O)CC2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: CCCOc1ccc2c(c1)C(N1CCNCC1)CC2

Procedure:
Piperazine (20.6 g, 0.24 mol), 6-(1-propoxy)indan-1-one (4.6 g, 24 mmol), titanium(IV) isopropoxide (16 ml, 48 mmol) and sodium borohydride (2.8 g, 74 mmol) were reacted by Method A to give the product which was converted to the fumarate salt (beige solid, 5.0 g, 55.4%, mp: 157°-159° C.). Calcd for C16H24N2O.C4H4O4.0.3H2O: C, 62.91%; H, 7.55%; N, 7.34%. Found: C, 62.70%; H, 7.45%; N, 7.07%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[O:16]1[CH2:19][C:18](=O)[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:16]1[CH2:19][CH:18]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CN(C2COC2)CCO1
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl morpholin-2-ylmethylcarbamate (0.50 g) in dichloromethane (5 mL) was added oxetan-3-one (0.20 g). After stirring for 5 minutes, sodium triacetoxyborohydride (0.735 g) was added. After stirring for 2 hours, the reaction was diluted with dichloromethane (50 mL) and quenched with saturated NaHCO3 solution (50 mL). The organic layer was separated, washed with brine (40 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 80 g) eluting with a gradient of 0.5% to 5% methanol/dichloromethane over 40 minutes (flow=40 ml/minute) gave the title compound.