Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[CH:24]1([CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[C:44]([F:46])[C:43]([O:47]C)=[CH:42][C:41]=3[F:49])[CH2:36][CH2:35]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:40]3[C:41]([F:49])=[CH:42][C:43]([OH:47])=[C:44]([F:46])[CH:45]=3)[CH2:38][CH2:39]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(F)c(N2CCN(CCCCC3CCCCC3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Oc1cc(F)c(N2CCN(CCCCC3CCCCC3)CC2)cc1F
Yield: 27.6 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(4-cyclohexylbutyl)-4-(2,5-difluoro-4-methoxyphenyl)-piperazine (482 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=16:1) to provide 4-[4-(4-cyclohexylbutyl)piperazin-1-yl]-2,5-difluorophenol (128 mg).
Reaction SMILES: I.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10](SC)=[NH:11].N[C:15]1[C:20]([OH:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=1[OH:24]>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[O:21][C:20]2[C:15](=[C:16]([OH:24])[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=2)[N:11]=1
Reactant: COc1cc(O)c(N)c(O)c1
Reactant: CSC(=N)c1cc(F)ccc1F
Agent: I
Solvent: CCO
Product: COc1cc(O)c2nc(-c3cc(F)ccc3F)oc2c1
Temperature: 78 °C
Reaction time: 5 h
Yield: 34.4 %

Procedure:
2.8 g (9.02 mmol; 1 equivalent) of methyl 2,5-difluorobenzene carbimidothioate hydroiodide in solution in 20 ml of ethanol is added to a solution of 1.4 g (9.02 mmol) of 2-amino-5-methoxybenzene-1,3-diol in 80 ml of ethanol. The reaction mixture is maintained under stirring at 78° C. for 5 hours then the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol mixture 98:2) and 860 mg (34% yield) of 2-(2,5-difluorophenyl)-6-methoxy-1,3-benzoxazol-4-ol is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:20](Cl)=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1.C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:20](=[O:21])[CH:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCCCCCCCC(CCCCCC)C(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCC(CCCCCC)C(=O)Nc1ccc(C(=O)OCC)cc1
Yield: 93.3 %

Procedure:
In a mixture of 40 ml of pyridine and 300 ml of acetonitrile was dissolved 82.5 g of 4-aminobenzoic acid ethyl ester and then 137.5 g of 2-hexyldecanoyl chloride was added dropwise to the solution thus formed at room temperature over a period of about 30 minutes. Thereafter, after keeping the mixture at 50° C. for 2 hours, the reaction mixture was allowed to cool and extracted with a mixture of ethyl acetate and an aqueous hydrochloric acid solution. The extract thus obtained was dried by magnesium sulfate and concentrated to provide 188 g of oily 4-(2-hexyldecanamido)benzoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH:36]([CH3:38])[CH3:37]
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 136, the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid isobutyl ester was prepared from 4-[(3R,4S)-3-(4-chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carbonitrile using isobutyl chloroformate instead of ethyl chloroformate and was obtained as a colorless foam. MS m/e: 524.5 [M]+.
Reaction SMILES: C([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:35][OH:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH:37]1[C:49]2[CH:48]([CH2:50][O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>N1CCCCC1.CN(C=O)C>[C:52]([NH:54][C@H:55]([C:60]([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:35][OH:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])([O:51][CH2:50][CH:48]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:49]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:53]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CO)Cc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
Dipeptide Fmoc-NH-L-Ile-D-Phe-CH2OH (1a) (520 mg, 1.06 mmol) was taken in 20% piperidine in DMF (2 mL) and stirred for 15 minutes at 25° C., TLC examination showed complete removal of the Fmoc protecting group (NH2-L-Ile-D-Phe-CH2OH), further confirmed by LC/MS examination, which showed M+−1 (263.3) peak. The reaction mixture was concentrated in vacuo, excess of the piperidine was removed by co-evaporating with toluene (2×10 mL), the free amino dipeptide was further dried over high vacumn for 30 minutes, and then redissolved in dry DMF (2 mL) and added to the mixture of N-(9-fluorenylmethoxycarbonyl)-L-leucine (38.1 mg, 1.06 mmol), DCC (262.0 mg, 1.27 mmol) and HOBt (171.4 mg, 1.27 mmol) in dry DMF (20 mL) at 25° C. The stirring was further continued for 14 h at 25° C. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (3% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.5), LC/MS also showed molecular ion peak corresponding to the tripeptide 2a with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 3% MeOH: CH2Cl2 to give 310 mg of the tripeptide Fmoc-NH-L-Leu-L-Ile-D-Phe-CH2OH (2a) as a white solid. Checked on LC/MS which showed M++1 (600.3) and M++Na (622.3).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][CH:6]1[CH2:11][C:10](=[O:12])[O:9][C:7]1=[O:8].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:19][C:13]1[CH:18]=[CH:17][C:16]([C:10]([CH2:11][CH:6]([CH3:5])[C:7]([OH:9])=[O:8])=[O:12])=[CH:15][CH:14]=1
Reactant: CC1CC(=O)OC1=O
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(C(=O)CC(C)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
Aluminium trichloride (50.7 g, 0.38 mol) is added, portionwise, over 15 min, to a solution of methylsuccinic anhydride (20 g, 0.175 mol), toluene (32.3 g, 0.35 mol) and nitrobenzene (100 ml). The reaction mixture is stirred for 3 hours and then warmed to 80° C. for half an hour. On cooling, it is quenched with water (75 ml) and then conc HCl (30 ml). The solid ppt. is filtered, dissolved in Na2CO3 solution, washed with CH2Cl2, re-acidified and the product filtered to yield 23.4 g of 3-(4-methylbenzoyl)-2-methyl-propionic acid as a white solid, m.p. 168°-170°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=O>CO.[Pd]>[CH2:8]1[C:9]2[C:5](=[C:4]([NH2:1])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1cccc2c1CCC2
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1CCC2
Reaction time: 14 h

Procedure:
4-Nitro-indan (5.00 g, 30.70 mmol) was dissolved in methanol, and Pd/C (500 mg) was added. The resulting reaction mixture was hydrogenated at 50 psi for 14 hours. Filtration through celite and concentration afforded the title indan-4-yl-amine.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:24]2=[O:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O1CCCC1>[OH:29][CH:24]1[C:25]2[C:20](=[C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH:23]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C1CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.3 %

Procedure:
To a solution of 5-t-butyldiphenylsilyloxy-2-ethoxycarbonyl-1-oxo-1,2,3,4-tetrahydronaphthalene (17 g) in a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml) was added NaBH4 (1.4 g) at 0° C. After the mixture was stirred for 6 hours at room temperature, the solvent was removed in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and the organic solution was washed with 1N-HCl solution, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-hydroxy-2-ethoxycarbonyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (7.9 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24](C(OC(C)(C)C)=O)[N:23]=[C:22]4[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[N:16]=[N:15]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[C:22]4[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[N:16]=[N:15]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(-c3ccc4c(c3)c(-c3ccncc3)nn4C(=O)OC(C)(C)C)nn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2n[nH]c3ccc(-c4cn([C@@H]5CCCNC5)nn4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the crude (R)-tert-butyl 5-(1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)-3-(pyridin-4-yl)-1H-indazole-1-carboxylate in CH2Cl2 (40 mL), added TFA (2.5 mL) and stirred at room temperature overnight under a stream of nitrogen. Evaporated the solvents and column purified (5-10% MeOH in CH2Cl2) to give (R)-5-(1-(piperidin-3-yl)-1H-1,2,3-triazol-4-yl)-3-(pyridin-4-yl)-1H-indazole (0.4 g).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=2)[C:8]1([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)O)[CH3:5]>CC(C)=O>[ClH:1].[CH3:3][N:4]([CH3:5])[CH2:6][C:7]1[CH2:15][C:14]2[C:9]([C:8]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:10][CH:11]=[C:12]([O:16][C:17]([F:20])([F:18])[F:19])[CH:13]=2
Reactant: CN(C)CC1Cc2cc(OC(F)(F)F)ccc2C1(O)c1cccnc1
Agent: Cl
Solvent: CC(C)=O
Product: CN(C)CC1=C(c2cccnc2)c2ccc(OC(F)(F)F)cc2C1
Reaction time: 8 h

Procedure:
About 10.8 ml of 37% hydrochloric acid were added at room temperature to 1.2 g of 2-dimethylaminomethyl-1-pyridin-3-yl-5-trifluoromethoxy-indan-1-ol hydrochloride (mixture of the diastereoisomers), and stirring was carried out overnight; 15 ml of acetone p.a. were added, and stirring was carried out for 2 hours. An oily, semi-crystalline precipitate formed, from which the supernatant was separated off. The residue was taken up in about 40 ml of acetone p.a. and stirred, whereupon fine crystals formed, which were filtered off with suction, with the exclusion of air, washed twice with diethyl ether and dried under an oil-pump vacuum at from 25 to 60° C. 1.17 g of dimethyl-(3-pyridin-3-yl-6-trifluoromethoxy-1H-inden-2-ylmethyl)-amine hydrochloride were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]1.[CH2:20]([SH:23])[CH2:21][SH:22].Cl[Si](C)(C)C>ClCCl>[S:22]1[CH2:21][CH2:20][S:23][CH:17]1[C:16]1[N:12]([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2([CH3:19])[CH3:1])[CH:13]=[N:14][CH:15]=1
Reactant: SCCS
Reactant: CC1(C)CCc2ccccc2C1n1cncc1C=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC1(C)CCc2ccccc2C1n1cncc1C1SCCS1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a stirred mixture of 5.1 parts of 1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazole-5-carboxaldehyde, 2.7 parts of 1,2-ethanethiol and 130 parts of dichloromethane were added dropwise 9.6 parts of chlorotrimethylsilane. Upon complete addition, stirring was continued overnight at 40° C. After cooling, the reaction mixture was washed with a potassium carbonate solution 10% in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.69 parts (55.8%) of 5-(1,3-dithiolan-2-yl)-1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazole; mp. 109.3° C. (compound 2.52).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:21]([N:28]1CCC(OCC(OC)=O)CC1)[C:22]1C=CC=CC=1.C(N)C>CO>[CH2:21]([NH:28][C:17](=[O:19])[CH2:16][O:15][CH:12]1[CH2:11][CH2:10][N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)[CH3:22]
Reactant: O=C(O)COC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)COC1CCN(Cc2ccccc2)CC1
Agent: CCN
Agent: Cl
Solvent: CO
Product: CCNC(=O)COC1CCN(Cc2ccccc2)CC1

Procedure:
2-(1-Benzylpiperidin-4-oxy)acetic acid, hydrochloride, prepared similarly to Preparation L Part A, was converted to its methyl ester by refluxing in methanol plus concentrated hydrochloric acid. Methyl 2-(1-benzylpiperidin-4-oxy)acetate (10 g) and ethylamine (50 ml) with 3 A molecular sieves were heated in a bomb at 120° for 6 hours. The solvent was then evaporated in vacuo, the residue triturated with ether, filtered and the filtrate evaporated to give N-ethyl-2-(1-benzylpiperidin-4-oxy)acetamide (7.7 g) as an oil. This product (7.0 g) in ethanol (150 ml) was hydrogenated over 5% palladium on charcoal (Engelhardt special debenzylation catalyst) at 50° and 50 p.s.i.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=[O:12])[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3Br)[CH2:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH:42]1([OH:47])[CH2:46][CH2:45][CH2:44][CH2:43]1>[Cu]I>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=[O:12])[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[O:47][CH:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH2:8][C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1C(=O)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: OC1CCCC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1nc(N)nc2c1C(=O)N[C@@H](c1ccc(F)cc1OC1CCCC1)C2
Temperature: 180 °C

Procedure:
A microwave vial was charged with (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, cesium carbonate (2 eq), copper (I) iodide (10 mol %), 1,10-phenanthroline (20 mol %), and cyclopentanol. The reaction mixture was heated with microwave irradiation to a temperature of 180° C. for 20 min. After cooling to RT, the reactionmixture was concentrated and purified by reverse phase HPLC to afford (R)-2-amino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (m/z=357 (M+H)).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[F:7][C:8]([F:12])([F:11])[CH2:9]I>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:8]([F:12])([F:11])[F:7])[CH:6]=1
Reactant: FC(F)(F)CI
Reactant: Ic1cn[nH]c1
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(I)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (960 mg, 5 mmol), 2,2,2-trifluoroethyl iodide (3.13 g, 15 mmol) and CS2CO3 (2.4 g, 7.7 mmol) in DMF (5 ml) is heated at 60° C. with stirring overnight. After cooling, the reaction mixture is partitioned between water (50 ml) and ether (20 ml). The organic layer is separated, dried (MgSO4) and concentrated to afford the title compound as an oil which solidified upon standing 1.0 g (72%). 1HNMR (CDCl3): δ (ppm) 4.70 (m, 2H), 7.56 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]3[C@@H:18]([CH2:26][OH:27])[O:17]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[S:38]([NH2:41])(=[O:40])=[O:39].C(#N)C>CN(C)C=O>[S:38](=[O:40])(=[O:39])([O:27][CH2:26][C@@H:18]1[C@@H:19]2[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[CH2:6][C:5]2[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=2)[O:17]1)[NH2:41]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(Cc3ccc(F)cc3)ncnc21
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(Cc3ccc(F)cc3)ncnc21
Reaction time: 1.5 h
Yield: 88 %

Procedure:
{(3aR,4R,6R,6aR)-6-[6-(4-Fluorobenzyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methanol (249 mg, 0.000622 mol) and triethylamine (173.4 μL, 0.001244 mol) were dissolved in dry N,N-dimethylformamide (10 mL) under nitrogen and the solution was cooled in a water/ice bath. A 2M solution of chlorosulfonamide in acetonitrile (0.0012 mol, 600 μL) was added dropwise. After 1.5 h, the reaction was quenched with methanol, concentrated in vacuo and the residue was purified by flash chromatography (DCM/EtOAc 30% to 80%) to obtain the product as an oil (262 mg, 88%).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].NC[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.C1(O)C=CC=CC=1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][CH2:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CCN(CC)C(=O)c1ccc(CCN)cc1
Solvent: Oc1ccccc1
Product: CCN(CC)C(=O)c1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.310 mmol), 4-(2-amino-ethyl)-N,N-diethyl-benzamide (0.082 g, 0.372 mmol) and phenol (1.0 g) were stirred at 135° C. for 2 hours. The reaction mixture was allowed to cool to r.t. and the product precipitated by the addition of MeOH (16 mL). The precipitate was filtered off and washed with MeOH to give the title compound. Yield: 0.058 g (40%). 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.61 (d, 2H, J=8.67 Hz), 7.39-7.44 (m, 3H), 7.30 (d, 2H, J=8.19 Hz), 7.18 (d, 2H, J=8.19 Hz), 4.23 (t, 2H, J=7.05 Hz), 3.51 (bs, 1H), 3.46 (d, 2H, J=5.39 Hz), 3.21 (bs, 1H), 3.12 (t, 2H, J=6.64 Hz), 1.21 (bs, 3H), 1.08 (bs, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)([O-:3])=[O:2].[H-].[Na+].N#N.[CH3:19]I>O.O1CCCC1.CN(C)C=O>[CH3:19][N:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-c1ncc[nH]1
Reactant: CI
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under N2, 9.5 g of 2-(2-nitrophenyl)-1H-imidazole in a solution of 100 ml dimethylformamide and 25 ml of anhydrous tetrahydrofuran cooled to 0°-5° C., was treated with 2.3 g of a 50% mineral oil dispersion of NaH. After the N2 evolution ceased, 8.5 g of CH3I was added dropwise over a period of 15 minutes maintaining the temperature at 0°-5°. The reaction mixture was allowed to warm to ambient temperature and then stirred for two hours. The reaction mixture was then poured into water. The aqueous suspension of the product was extracted several times with CH2Cl2. The extracts were combined and dried with anhydrous Na2SO4. The solvent was removed on a rotary evaporator. The last traces of dimethylformamide were removed under high vacuum; a waxy solid remained. The crude product was crystallized from CH3CN. Two crops totaling 3.6 g were obtained. The m.p. was 89°-90°.
Reaction SMILES: ClCCl.B(Br)(Br)Br.C(Cl)(Cl)Cl.C[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]3[CH:32]=[CH:31][N:30]=[CH:29][C:22]=3[C:23]3[N:24]([CH:26]=[N:27][N:28]=3)[N:25]=2)=[CH:16][CH:15]=1>O>[N:28]1[N:27]=[CH:26][N:24]2[C:23]=1[C:22]1[CH:29]=[N:30][CH:31]=[CH:32][C:21]=1[C:20]([C:17]1[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=1)=[N:25]2
Reactant: COc1ccc(-c2nn3cnnc3c3cnccc23)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Oc1ccc(-c2nn3cnnc3c3cnccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.3 %

Procedure:
4.0 ml (4.0 mmol) of a dichloromethane solution of 1 M boron tribromide was added to a chloroform solution (10 ml) of 417 mg of 6-(4-methoxyphenyl)-pyrido[3,4-d][1,2,4]triazolo[4,3-b]pyridazine, and then stirred overnight at room temperature. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 421 mg of 4-(pyrido[3,4-d][1,2,4]triazolo[4,3-b]pyridazin-6-yl)-phenol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[NH:12]C(=O)C)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>CCO>[C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[NH2:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(Cl)cc1C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(Cl)ccc1N
Temperature: 110 °C
Reaction time: 5 h
Yield: 110.2 %

Procedure:
A mixture of N-(2-tert-butyl-4-chlorophenyl)acetamide (Reference Example 18, 4.78 g, 21.2 mmol), concentrated HCl (50 mL) and EtOH (10 mL) was stirred at 110° C. for 5 h. After cooling, the reaction mixture was basified with 8 M NaOH under ice-cooling. The mixture was extracted with ethyl acetate and the organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.29 g) as a colorless oil.