Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:24]=[CH:25][C:18]=12>C1COCC1.C(OCC)(=O)C>[Cl:32][C:31]1[C:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6])=[C:18]3[CH:25]=[N:24]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
Sodium hydride (62.4 mg, 1.56 mmol) was to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (200 mg, 1.04 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (360 mg, 1.35 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (245 mg, 55.8%). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, 3H), 3.33-3.48 (m, 5H), 3.74-3.82 (m, 4H), 4.13-4.18 (m, 2H), 5.81-5.86 (m, 1H), 7.43-7.48 (m, 1H), 7.98-8.02 (m, 1H), 8.39-8.41 (m, 1H), 8.58 (s, 1H), 8.60-8.63 (m, 1H); m/z (ESI+) (M+H)+=422.36; HPLC tR=1.93 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH2:48][CH2:49][CH3:50])(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH2:48][CH2:49][CH3:50])(=[O:45])[OH:46])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CCCCP(=O)(O)CCCN
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCCP(=O)(O)CCCNC(=O)O[C@@H](OC(=O)C(C)C)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet was added compound (25) (100 mmol), 3-aminopropyl(n-butyl)phosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension was stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture became homogeneous. The THF was removed in vacuo and the reaction mixture was diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase was separated and concentrated in vacuo to leave a white solid. The solid was purified by flash chromatography to afford the product (39) as a white solid. 1H-NMR (400 MHz, CD3OD): δ 6.74-6.70 (q, J=5.2, 1H), 4.06-3.96 (m, 1H), 3.22-3.21 (m, 2H), 2.547-2.477 (m, 1H), 1.92-1.84 (m, 2H), 1.52-1.48 (s, 3H), 1.142-1.138 (d, J=1.6, 3.0H), 1.124-1.121 (dd, J=1.6, 3.0H). Phosphorus (162 MHz, CD3OD): δ1.04; MS (ESI) m/z 346 (M+H)+)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:50]([CH3:49])(=[O:52])=[O:51])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of methanesulfonyl chloride (32 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 4 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, washed with pentane and dried to afford the title compound as a solid (80 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C)C=O.O>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC[C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of methyl 4-(4-hydroxyphenyl)benzoate (0.94 g), (S)-(−)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-1-propanol (1.00 g) and triphenylphosphine (1.62 g) in N,N-dimethylformamide (20 ml) was added dropwise diisopropyl azodicarboxylate (1.21 ml) for 10 minutes under ice-cooling in a stream of nitrogen. The solution was stirred for 16 hours at ambient temperature, and then water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixed solvent of n-hexane-ethyl acetate (from 0% to 20% gradient elution) to give methyl (S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoate (290 mg) as a white solid.
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([SH:16])[N:11]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH:2]2[S:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])[N:11]=1
Reactant: Cc1cccc(S)n1
Reactant: O=C1NC(=O)C(Br)S1
Product: Cc1cccc(SC2SC(=O)NC2=O)n1

Procedure:
This compound was prepared from 5-bromo-thiazolidine-2,4-dione and 2-methyl-6-mercaptopyridine (A. D. Dunn, R. Norfie, J. L'Hostis,and S. Marjot J.Prak. Chem.-Chem. Zt. 1992, 334, 119-125) according to the procedure described in Example 1: mp 114-115.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].[CH3:12]NCCC[Si](OC)(OC)OC.C[Si](OC(=O)C)(OC(=O)C)OC(=O)C.C[Si](OCC)(OCC)OCC.C[Si](OC)(OC)OC>>[SH:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CO[Si](CCCS)(OC)OC
Reactant: CNCCC[Si](OC)(OC)OC
Agent: CC(=O)O[Si](C)(OC(C)=O)OC(C)=O
Agent: CCO[Si](C)(OCC)OCC
Agent: CO[Si](C)(OC)OC
Product: CO[Si](C)(CCCS)OC

Procedure:
Mercaptopropyltrimethoxysilane; N-methylaminopropyltrimethoxysilane; Methyltriacetoxysilane; Methyltriethoxysilane; Methyl trimethoxysilane;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3O)[N:4]=1.P(Cl)(Cl)([Cl:25])=O>O>[Cl:25][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Solvent: O
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Cl)n1
Temperature: 90 °C

Procedure:
2.3 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) are suspended in approximately 40 ml of phosphorus oxychloride, and the suspension is heated at 90° C. for 2 hours. The reaction mixture is then introduced at from 35° to 45° C. into 250 ml of water. It is then diluted with a further 500 ml of water and the crystals which separate are filtered off and washed neutral with water to yield pure 3-chloro-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide in the form of slightly yellowish crystals, m.p. 143°-144° C.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])=[CH:38][N:37]=2)=[CH:11][N:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:45]([S:42]([C:39]1[CH:40]=[CH:41][C:36]([C:12]2[CH:13]=[C:14]([C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([CH2:26][NH:27][CH3:28])=[CH:24][CH:25]=4)=[N:17][N:16]=3)[C:9]([NH2:8])=[N:10][CH:11]=2)=[N:37][CH:38]=1)(=[O:43])=[O:44])([CH3:47])[CH3:46]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2nnc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16 %

Procedure:
The residue from Method F Step 2 was dissolved in DCM (10 mL) and TFA (2 mL, 25.96 mmol) was added. The reaction was stirred at ambient temperature for 15 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as an off-white solid (11.4 mg, 16% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.23 (d, J=6.8 Hz, 6H), 2.30 (s, 3H), 3.56 (sept, 1H), 3.77 (s, 2H), 7.60 (d, 2H), 7.91 (s, 2H), 8.16 (d, 2H), 8.29 (dd, 1H), 8.36 (d, 1H), 9.00 (d, 1H), 9.03 (d, 1H) and 9.12 (d, 1H) ppm; MS (ES+) 465.3.
Reaction SMILES: [CH2:1]([NH:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1.C(O)C.[H][H]>N1C=CC=CC=1>[CH2:1]([NH:22][C:23](=[O:35])[C:24]1[CH:25]=[CH:26][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=1)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=1
Reactant: O=C(NCCC#CCCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Reactant: [H][H]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(NCC/C=C\CCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
A solution containing 9.86 g. of N,N'-(3-heptyne-1,7-diyl)bis(4-trifluoromethoxybenzamide) in 110 ml. of ethanol and 5.0 ml. of pyridine was hydrogenated in a Parr shaker using 1.0 g. of palladium-on-barium sulfate using an initial pressure of hydrogen of 35.5 psi and taking about 40 minutes. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo to remove the sulfate. The white crystalline solid residue was recrystallized from carbon tetrachloride using a small quantity of methanol to yield, as a white microcrystalline powder after drying in vacuo at 60° C. for about 50 hours, 7.6 g. of N,N'-(cis-3-heptene-1,7-diyl)bis(4-trifluoromethoxybenzamide), m.p. 111°-113° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:26]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)c1ccccc1)c1ccc(OC)c(OC)c1
Yield: 100.2 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (0.689 grams, 2.50 mmol) and triethylamine (0.7 milliliters, 5 mmol) in 15 milliliters of tetrahydrofuran was added 0.3 milliliters of benzoyl chloride (2.6 mmol). The cooling bath was removed after 15 minutes and the mixture stirred for an additional 45 minutes. The reaction mixture was then diluted with 15 milliliters of brine and 15 milliliters of water and then partially concentrated in vacuo to remove the tetrahydrofuran. The reaction slurry was filtered, the solid air-dried, then dried in vacuo (60° C., <1 mm) to afford 0.86 g (100%) of the product as a white powder: 1H NMR (dmso-d6, 250 MHz) δ 8.84 (d, J=8.3 Hz, 1 H, NH), 7.83 (m, 2 H, Ar), 7.60-7.35 (m, 3 H, Ar), 7.06 (s, 1 H, Ar), 6.90 (m, 2 H, Ar), 5.50-5.30 (m, 1 H, CHN), 3.75 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.46 (s, 3 H, CO2CH3), 3.05-2.75 (m, 2 H, CH,); 13C NMR (dmso-d6) δ 17 165.6, 148.6, 147.9, 134.9, 134.5, 131.2, 128.3, 127.3, 118.5, 111.6, 110.6, 55.5, 55.5, 51.4, 49.7, 40.6. Anal. Calcd for C19H21,NO5. Theoretical C, 66.46; H, 6.16; N, 4.08. Found C, 66.22; H, 6.05; N, 3.98.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>CN(C=O)C>[C:26]1(=[O:35])[N:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2)=NN1
Temperature: 100 °C

Procedure:
A mixture of 2.00 g (10.5 mmol) of 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared as described in Example 13, 1.60 g (11.6 mmol) of anhydrous K2CO3, and 3.39 (1.26 mmol) of N-(bromopropyl)phthalimide in 43 ml of DMF is heated at 100° C. for 3 hrs under N2. The DMF is removed under vacuum and the residue taken up in 125 ml of EtOAc and 50 ml of water. The organic phase is washed with 50 ml of 5% aqueous NaOH, then with saturated NaCl, dried (MgSO4), and the solvent removed to leave a yellow solid. This solid is recrystallized from EtOAc to give 2.748 g of 6-[4-(3-phthalimidopropyloxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 69%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.BrC1C=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][C:32]=2[CH:33]=1)[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:25]([C:29]1[O:30][C:31]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:34][C:32]=2[C:33]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(O)c1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(Br)cc1

Procedure:
5.08 g of 4-bromobenzoyl chloride—prepared by reacting 4-bromobenzoic acid with thionyl chloride—and 5.42 g of 2-butyl-5-methanesulfonamido-benzofuran (IV) were dissolved in 30 ml of dichloromethane. The reaction was performed according to Example 10.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.C(N(CC)CC)C.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C(Cl)Cl>[Si:26]([O:10][CH2:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]2[N:5]([N:12]=[CH:13][CH:14]=2)[C:6]=1[Cl:11])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1c(Cl)nc2ccnn2c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1c(Cl)nc2ccnn2c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.4 %

Procedure:
To a methylene chloride (50 mL) solution containing 2-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)ethanol (640 mg, 2.77 mmol), triethylamine (3.86 mL, 27.7 mmol) and tert-butylchlorodimethylsilane (1.25 g, 8.31 mmol) were added, and this mixture was stirred at room temperature for 16 hr. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (15% ethyl acetate-hexane) to obtain the title compound (1.04 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[H][H]>[Ni].CC(N(C)C)=O.CO>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Ni]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CN(C)c1ccc(N)c(C(=O)O)c1

Procedure:
A mixture of 18 g. of 2-nitro-5-dimethylaminobenzoic acid, 1.0 liter of a 50:50 mixture of dimethylacetamide/methanol and 18 g. of Raney Nickel is hydrogenated at a hydrogen pressure of 40-50 psi for 2 hours. The resulting mixture is filtered, washed with methanol and the total filtrate evaporated to a solid which is broken up, washed with ether and dried to obtain 2-amino-5-dimethylaminobenzoic acid, m.p. 231°-234° C. (decomp.).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[C:12]([C:13]=1[CH3:14])=[CH:11][C:10]([OH:15])=[CH:9][CH:8]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C=O)C.O>[OH:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[O:6][C:5](=[O:16])[C:4]([CH2:3][CH2:2][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[C:13]2[CH3:14]
Reactant: C1CCNC1
Reactant: Cc1c(CCBr)c(=O)oc2ccc(O)cc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CCN2CCCC2)c(=O)oc2ccc(O)cc12
Temperature: 25 °C
Yield: 250.9 %

Procedure:
A solution of Example 41A (0.20 g, 0.70 mmol) and pyrrolidine (0.50 mL, 6.0 mmol) in DMF (2 mL) was heated to 75° C. for 16 hours, cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate was dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica with 10% methanol in dichloromethane to give the titled compound (0.48 g, 25%). MS (DCI) m/z 274 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43]>ClCCl>[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:23][CH:24]=1)=[O:43]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.644 g, 5.1 mmol) was added, and dissolved in 30 mL dichloromethane. Triethylamine (2.13 mL, 15.3 mmol) was added, and in an ice bath a dichloromethane solution dissolving 2-naphthoyl chloride (1.067 g, 5.6 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 1 h, and stirred at room temperature overnight. It was filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 0.53 g, at a yield of 21.8%.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=2[N+]([O-])=O)[C:13]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl-].[Na+]>CN1CCN(C)C1=O.O>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=2[S:2][CH3:1])[C:13]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C[S-]
Reactant: O=C(OC1CCCC1)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CSc1ccc(C(=O)OC2CCCC2)cc1OC1CCCC1
Reaction time: 4 h
Yield: 81.1 %

Procedure:
Sodium thiomethoxide (0.177 g, 2.5 mmol) is added portionwise to a stirred solution of cyclopentyl 3-cyclopentyloxy-4-nitrobenzoate (0.64 g, 2 mmol) in N,N'-dimethylimidazolidinone (10 mL) at ambient temperature under an atmosphere of nitrogen and stirring continued for 4 hours. The mixture is then diluted with water (100 mL) containing sodium chloride (15 g) and extracted with ethyl acetate (2×50 mL). The combined extract is washed with saturated brine (1×100 mL) and then dried over magnesium sulfate and evaporated under reduced pressure to give cyclopentyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.52 g, 81%) as a brown viscous oil which is used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13]CC3C=CC=CC=3)[CH:6]=[CH:5][C:4]1=2.[ClH:22].[H][H]>C(O)C.CC(O)C.[Pd]>[ClH:22].[CH3:21][C:3]1([NH:2][CH3:1])[CH2:12][CH2:11][CH2:10][C:9]2[NH:8][C:7](=[O:13])[CH:6]=[CH:5][C:4]1=2
Reactant: CNC1(C)CCCc2nc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CNC1(C)CCCc2[nH]c(=O)ccc21
Yield: 25 %

Procedure:
5,6,7,8-Tetrahydro-N,5-dimethyl-2-(phenylmethoxy)-5-quinolinamine (6.3 g) in ethanol (500 ml) was acidified to ca pH2 with a solution of hydrochloric acid in 2-propanol. 10% Palladium-on-carbon (315 mg) was added and the mixture was shaken on Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst was collected and the filtrate was neutralized with 4-polyvinylpyridine. The solution was concentrated in vacuo to a volume of about 75 ml and diethyl ether was added. The precipitate was collected and recrystallized first from methanol and then from water/2-propanol to afford 1.3 g (25%) of product, mp 190°-195° C. (dec).