Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C([Li])CCC.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[F:24])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: O=C(Cl)c1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(C(=O)c3ccccc3F)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.22 mmol) dissolved in THF (25 ml) was cooled to -78° C., and 2.5 ml of n-butyllithium (1.27M in hexane) were added. After one hour, o-fluorobenzoyl chloride (0.38 ml, 3.22 mmol) was added. The mixture was stirred for 10 minutes at -78° C. after which the reaction was quenched by addition of water at -78° C. The reaction was made basic with NaOH and extracted three times with methylene chloride. The basic extract was dried (Na2SO4) and concentrated to give 2.0 g of crude residue. Purification of this material by flash silica gel chromatography using 1:1 ether:hexane containing a trace of ammonium hydroxide as solvent provided 2-di-n-propylamino-8-(2'-fluorobenzoyl)-1,2,3,4-tetrahydronaphthalene (340 mg).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:7]=1[CH2:8][NH:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([C@H:19]3[C@@H:23]4[O:24][C:25]([CH3:28])([CH3:27])[O:26][C@@H:22]4[C@@H:21]([CH2:29][N:30]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:31]4[CH2:34][CH:33]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[CH2:32]4)[CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1.O1CCCC1.CO.Cl>>[CH3:4][O:5][C:6]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:7]=1[CH2:8][NH:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([C@H:19]3[C@@H:23]4[O:24][C:25]([CH3:27])([CH3:28])[O:26][C@@H:22]4[C@@H:21]([CH2:29][N:30]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:31]4[CH2:32][CH:33]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:34]4)[CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)CCC1CC(N(CC(C)C)C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Lithium hydroxide, monohydrate (1.11 g, 26.4 mmol) was added to a solution ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isobutyl)amino)cyclobutyl)propanoate (1.75 g, 2.64 mmol) in Tetrahydrofuran (13 ml, 160 mmol) and Methanol (3 ml, 70 mmol). The reaction was stirred for 24 hours at RT, acidified with 1 N HCl to pH=6, the volatiles removed in vacuo and remaining water removed by azeotropic distillation with ethanol followed by 18 hours on lyophilizer. The resulting off white solid was used without further purification.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].CN1[CH:11]=[CH:10]N=C1.[C:12]1(C)[C:17]([OH:18])=[CH:16][CH:15]=C[CH:13]=1>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:18][C:17]1[CH:12]=[CH:13][C:10]([CH3:11])=[CH:15][CH:16]=1
Reactant: Cn1ccnc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1O
Product: Cc1ccc(OP(=O)(Cl)Cl)cc1
Reaction time: 2 h

Procedure:
To a mixture of 225 g. phosphoryl chloride and 1.6 g. 1-methylimidazole there is added 109 g. cresol over a period of 2 hours at a temperature of 105°C. The temperature is held at 105°-110°C. for two hours to afford cresyl phosphorodichloridate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3/[CH:16]=[CH:17]\Cl)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(/C=C\Cl)c2[C@@H]2CCCN12
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
2.5 g (7.5 mmol) of (S)-8-chloro-1-[(Z)-2-chlorovinyl]-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was heated to boiling under reflux for 5 hours together with 1.66 ml (11.2 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into 400 ml of water and the crystals obtained were filtered off. After drying and recrystallization from N,N-dimethylformamide there was obtained (S)-8-chloro-1-ethynyl-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 324°-325°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[C:20]([C:22](O)=[O:23])[O:19][N:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][C:29](=[O:36])[C@@H:30]([NH2:35])[CH2:31][CH:32]([CH3:34])[CH3:33].[K+].[Br-]>>[CH3:27][O:28][C:29](=[O:36])[C@@H:30]([NH:35][C:22]([C:20]1[O:19][N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:25])=[CH:16][CH:15]=2)[CH:21]=1)=[O:23])[CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1
Yield: 69.5 %

Procedure:
The title compound was prepared from 3-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-isoxazole-5-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 69.5% yield. Mass (ES+): 469 (M++1); IR (KBr): 3312 (br), 2960, 1743, 1665 (br), 1612, 1597, 1542 (br), 1508; 1H NMR (DMSO-d6) δ: 0.85, 0.90 (2×d, 6H), 1.59 (m, 2H), 1.79 (m, 1H), 3.64 (s, 3H), 4.47 (m, 1H), 7.11 (t, 1H), 7.45 (m, 2H), 7.58 (d, 2H), 7.60 (s, 1H), 7.82 (d, 2H), 8.78 (sr, 1H), 8.95 (s, 1H), 9.32 (d, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[O:14][CH2:15]C)#[N:2].O.[OH-].[Li+].Cl>CO.C1COCC1.O>[C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])#[N:2]
Reactant: CCOc1cc(C(=O)OC)ccc1CC#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1CC#N

Procedure:
A solution of methyl 4-(cyanomethyl)-3-ethoxybenzoate (18 g, 88 mmol) in 150 mL of MeOH:THF:H2O (3:3:1) was treated with lithium hydroxide monohydrate (11 g, 263 mmol) at 22° C. for overnight. Then 10% aqueous HCl (100 mL) was added to quench the reaction, the mixture was extracted with EtOAc (3×200 mL), the combined organic extracts were washed with brine (100 mL) and dried (MgSO4), filtered and concentrated in vacuo to afford 4-(cyanomethyl)-3-methoxybenzoic acid as a white solid. MS (ESI) 192 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15](=[O:20])[CH2:14][CH2:13]2.C(O)(=O)C>C1(C)C=CC=CC=1.O>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:3]([O:6][CH3:7])=[O:8])=[C:15]([OH:20])[CH2:14][CH2:13]2
Reactant: O=C1CCc2cc(F)ccc2C1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(O)CCc2cc(F)ccc21
Temperature: 0 °C
Yield: 102.1 %

Procedure:
12.66 g (316 mmol) of 60% sodium hydride in oil, 900 ml of toluene and 17.69 ml (210 mmol) of dimethyl carbonate are introduced into a 2 l reactor. The reaction mixture is stirred at reflux for 1 h. A solution of 19 g (115 mmol) of 6-fluoro-3,4-dihydro-1H-naphthalen-2-one in 350 ml of toluene is subsequently added. The reaction mixture is heated at reflux for 24 h. The reaction mixture is subsequently cooled to 0° C. and then acidified by addition of 114 ml of acetic acid. 114 ml of water are added and the separated organic phase is separated by settling and washed with two times 150 ml of water and then with 100 ml of a saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulphate and then concentrated under reduced pressure to result in 26.1 g of a product which is used as is in the following stage.
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[N:10]=[C:9]([SH:14])[N:8]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>O>[OH:6][C:7]1[CH:12]=[C:11]([OH:13])[N:10]=[C:9]([S:14][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[N:8]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1cc(O)nc(S)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CSc2nc(O)cc(O)n2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
A DMF (500 ml) solution of 4,6-dihydroxy-2-mercaptopyrimidine (50 g, 346 mmol), triethylamine (62.7 ml, 450 mmol), 4-methoxybenzyl chloride (52.8 ml, 381 mmol) was heated and stirred at 100° C. for 1 hour 45 minutes. The reaction solution was poured into water and stirred for a while, and the precipitated crystals were collected by filtration and air-dried to obtain 75.2 g (82% yield) of 4,6-dihydroxy-2-(4-methoxybenzylsulfanyl)pyrimidine.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH2:14][C:15](=[O:18])[CH2:16][CH3:17].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]([OH:33])[CH:14]([CH3:13])[C:15](=[O:18])[CH2:16][CH3:17])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCC(=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(=O)C(C)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A solution of diisopropylamine (0.63 mL, 4.5 mmol) in THF (16 mL) at 0° C. was treated with 1.6 M n-butyllithium in sol'n in hexanes (2.8 mL). The resulting solution was stirred at 0° C. for 10 min, then cooled to −78° C. 3-Pentanone (0.41 mL, 4.1 mmol) was added and the resulting mixture was stirred cold for 1 h. A solution of 1-(t-butoxycarbonyl)-4-formylpiperidine (435 mg, 2.05 mmol) (from Step B) in THF (3 ml) was then added. After 15 min, the reaction was quenched with sat'd ammonium chloride (25 mL) and extracted with ether (100 mL). The extract was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 4:1 v/v, then 3:2 v/v hexanes/ethyl acetate as the eluent afforded 517 mg (85%) of the title compound.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[N:24][CH:25]=1.C[Si](C)(C)[C:31]([F:34])([F:33])[F:32]>C1COCC1.O>[Br:19][C:20]1[CH:21]=[C:22]([C:26]([OH:28])([CH3:27])[C:31]([F:34])([F:33])[F:32])[CH:23]=[N:24][CH:25]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1cncc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1cncc(Br)c1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 33 μl, 0.033 mmol) was added to a solution of 1-(5-bromopyridin-3-yl)ethanone (65 mg, 0.33 mmol) and trimethyl(trifluoromethyl)silane (92 mg, 0.65 mmol) in THF (1.1 mL) at ambient temperature. After 30 minutes, the reaction mixture was diluted with water and extracted with DCM, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate/hexanes, linear gradient) to afford 2-(5-bromopyridin-3-yl)-1,1,1-trifluoropropan-2-ol. MS ESI calc'd. for C8H8BrF3NO [M+H]+ 270 and 272. found 270 and 272. 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 8.69 (d, J=2.5 Hz, 1H), 8.10-8.08 (m, 1H), 2.58 (s, 1H), 1.82 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=2)[NH:7][CH:6]=1)[CH3:4].C[N:20](C=O)C>>[CH2:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][C:15]([F:18])([F:16])[F:17])[CH:12]=2)[N:7]([NH2:20])[CH:6]=1)[CH3:4]
Reactant: CN(C)C=O
Reactant: CCc1c[nH]c2ccc(OC(F)(F)F)cc12
Agent: [H-]
Agent: [Na+]
Product: CCc1cn(N)c2ccc(OC(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A suspension of NaH (7.9 g, 197 mmol, 60% in mineral oil) in DMF (60 mL) at 0° C. is treated with 3-ethyl-5-trifluoromethoxy-1H-indole (3 g, 13.1 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (7.4 g, 65.5 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice and filtered through a pad of Celite. The filtrate is extracted with heptane (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-30% EtOAc in heptane to afford 3-ethyl-5-trifluoromethoxy-indol-1-ylamine (2.05 g, 64%). MS: 245 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.37 (m, 2H), 7.11 (m, 1H), 7.00 (s, 1H), 4.72 (s, NH2, 2H), 2.73 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CC[C@@H](N)C[C@H]1F
Product: CC(=O)N[C@@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f67) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.[Cl:23][CH:24]([Cl:28])[C:25]([OH:27])=[O:26]>>[Cl:23][C:24]([Cl:28])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(C)(C)c1ccc(OCCCCCCCCCCBr)cc1
Product: CC(C)(C)c1ccc(OCCCCCCCCCCC(Cl)(Cl)C(=O)O)cc1
Yield: 33.5 %

Procedure:
6.8 g (20 mmol) 92 was reacted with 10.3 g (80 mmol) dichloroacetic acid as in example 9. 2.8 g (35%) 41 with a melting point of 56-57° C. was obtained. The sodium salt obtained from 41 and pulverized NaOH in ethanol melted at 178° C. (decomp.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:31][CH2:32][CH3:33])[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]=1[C:8]([O:10]CC)=[O:9].O.[OH-].[Li+].Cl>O>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:31][CH2:32][CH3:33])[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A mixture of 0.20 g of ethyl 4-hydroxymethyl-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 35(c)] and 0.10 g of lithium hydroxide monohydrate in 3 ml of water was stirred at room temperature for 3 hours, after which it was allowed to stand for 16 hours at the same temperature. The reaction mixture was then mixed with 2.38 ml of 1N aqueous hydrochloric acid and the resulting precipitate was collected by filtration, to give 150 mg of the title compound, melting a=233° C. (with decomposition).
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][N:22]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1.Cl.C(OCC)(=O)C>C(OCC)C>[ClH:20].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:21]2[N:22]=[CH:23][C:24]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=3)=[CH:25][CH:26]=2)=[CH:31][CH:30]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: OB(O)Oc1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)nc2)cs1)C(=O)O

Procedure:
A compound obtained by an operation similar to that of Example 67-1 and using 2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 4 and 2-chloro-5-hydroxypyridine synthesized in reference to patent reference [WO9825920] as starting materials, followed by an operation similar to that of Example 68 and using 4-fluorophenylboric acid was dissolved in diethyl ether and the solution was reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: C([O:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][NH:23][C:15]3=[N:14][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][NH:23][C:15]3=[N:14][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Yield: 80 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H,3H)-dione (100 mg, 0.276 mmol) and a 1.0 M solution of hydrogen chloride in diethylether(1.0 ml, 1.0 mmol) in methanol (15 ml) was stirred at 70° C. for 3 hours. Concentration under reduced pressure provided (R)-3-(5-hydroxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H, 3H)-dione (CT-13431) (71 mg, 80% yield) as a white powder.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[CH2:17][CH3:18]>O>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[N:2][OH:3])[CH2:17][CH3:18]
Reactant: CCC(=O)c1cccs1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Hydroxylamine hydrochloride (3.2 g, 46.3 mmol) and sodium acetate (3.8 g, 46.3 mmol) were added to 20 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(Thiophen-2-yl)propan-1-one (5.9 g, 42.1 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (20 mL) was added and the product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 6.3 g of the title compound. MS: (+) m/z 156.32 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH:14]=1)([O-])=O.O.NN.N.C(Cl)Cl>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1
Agent: [Ni]
Agent: N
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1
Yield: 86.9 %

Procedure:
A solution of 2-(4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (0.225 g, 0.783 mmol) in dry methanol (5 mL) was treated with hydrazine hydrate (0.244 mL, 7.83 mmol), followed by Raney-nickel (0.1 g, 0.783 mmol) at room temperature. The resulting mixture was placed in a pre-heated oil bath and refluxed for 5 minutes (TLC basis, 2 M NH3 in MeOH:CH2Cl2, 1:9). The reaction was brought to room temperature, filtered through a Celite bed, and washed with methanol (3×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain 2-(4-(5-amino-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (0.175 g, 87%) as a solid. 1H NMR (DMSO-d6) δ 10.59 (s, 1H), 7.15 (d, 1H, J=2.4 Hz), 7.05 (d, 1H, J=8.4 Hz), 6.99 (s, 1H), 6.48 (dd, 1H, J=1.8, 8.4 Hz), 5.96 (s, 1H), 4.48 (brs, 2H), 4.40 (t, 1H, J=5.4 Hz), 3.55 (q, 2H), 3.16-3.10 (m, 2H), 2.65 (t, 2H, J=5.7 Hz), 2.50-2.45 (m, 4H); ESI-MS (m/z, %): 258 (MH+, 30), 185 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:21]1[CH2:25][CH2:24][N:23]([C@@H:26]([CH3:35])[C:27](=[O:34])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:22]1=[O:36])[CH2:16][C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Li+].Cl>C1COCC1.O>[ClH:1].[CH3:17][OH:18].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:21]1[CH2:25][CH2:24][N:23]([C@@H:26]([CH3:35])[C:27](=[O:34])[N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:22]1=[O:36])[CH2:16][C:17]([OH:19])=[O:18])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCCCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CO
Product: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](N(CC(=O)O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Yield: 10 %
Yield: 205.4 %

Procedure:
To a solution of methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate (0.010 g) in THF (1 ml) was added lithium hydroxide (0.005 g) in water (1 ml), and the resultant solution stirred for 16 h. The mixture was acidified to pH5 using hydrochloric acid (2N), and then concentrated under reduced pressure. The residue was purified using SPE (eluting with methanol and then 10% HCl/methanol) to give the title compound (0.01 g) as a white solid.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:16]([O:23][CH2:24][C:25]([OH:27])=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:28]([NH:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1.O>[CH2:28]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[C:25](=[O:27])[CH2:24][O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:29][CH2:30][CH3:31]
Reactant: O=C(O)COCc1ccccc1
Reactant: CCCCNCCCC
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCN(CCCC)C(=O)COCc1ccccc1
Reaction time: 0.17 h

Procedure:
3 g of N-methylmorpholine and 4 g of isobutyl chloroformate were successively added dropwise to 5 g of 2-benzyloxyacetic acid in 50 ml of THF at −10° C. The mixture was stirred for 10 minutes and then 5 ml of di-n-butylamine and a further 3 g of N-methylmorpholine were added. After one hour, the mixture was added to 500 ml of water and extracted several times with ether. The collected organic phases were dried over magnesium sulfate and, after removal of the solvent by distillation, 7 g of an oil were isolated and were immediately employed further.