Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH:11]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=2[CH3:22])[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:18]([CH3:20])=[CH:17][C:16]([CH3:21])=[C:15]([CH3:22])[C:14]=3[O:13][C:11]=2[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(C)c(OC(C)C(=O)c2ccc(C(C)C)cc2)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(-c3ccc(C(C)C)cc3)c(C)oc2c1C
Temperature: 80 °C
Yield: 96 %

Procedure:
A mixed solution of 1-(4-isopropylphenyl)-2-(2,3,5-trimethylphenoxy)propan-1-one obtained in Reference Example 346 (61.3 g, 194 mmol), Amberlyst 15 (61.0 g) and a molecular sieve MS 4A (30 g) in toluene (200 mL) was heated under reflux at 80° C. for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane 1:100) to obtain 54.4 g (yield 96%) of the title compound. Oily matter.
Reaction SMILES: [CH:1]([N:4]([CH:28]([CH3:30])[CH3:29])[C:5](=[O:27])[O:6][C:7]1[C:15]2[C:14]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:8]=1)([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.Cl.C(O)(C)C>[ClH:20].[CH:28]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:27])[O:6][C:7]1[C:15]2[C:14]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=3[CH:12]=[CH:11][C:10]=2[N:9]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:8]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N(C(=O)Oc1nn(-c2ccncc2)c2c1-c1ccc(Cl)cc1CC2)C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)O
Product: CC(C)N(C(=O)Oc1nn(-c2ccncc2)c2ccc3cc(Cl)ccc3c12)C(C)C
Yield: 153.8 %

Procedure:
1.65 g (3.38 mmol) of 7-chloro-4,5-dihydro-3-(pyrid-4-yl)-3H-benzo[e]indazol-1-yl N,N-diisopropylcarbamate, prepared according to the method described in Example 5, 1.105 g (6.21 mmol) of N-bromosuccinimide and 0.127 g (0.78 mmol) of 2,2′-azobis(2-methylpropionitrile) are added to a 100 ml reactor. The mixture, dissolved in 40 ml of carbon tetrachloride, is stirred at reflux for 24 h and is then concentrated under reduced pressure. The resulting product is taken up in 300 ml of dichloromethane and 2 ml of a concentrated aqueous ammonia solution. The organic phase is separated and washed with 200 ml of water and then with 200 ml of a saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulphate and then concentrated under reduced pressure. The resulting product is purified by chromatography on an alumina column (eluents: mixture of dichloromethane and of methanol) and then on a silica column (eluents: mixture of dichloromethane and of ethyl acetate). The product thus isolated is converted to the hydrochloride by dissolution in a 0.1N solution of hydrochloric acid in isopropanol. The solution is concentrated to dryness under reduced pressure. After triturating from ethyl ether, filtering off and drying under reduced pressure, 1.2 g (2.6 mmol) of the final product are obtained.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][NH2:16])=[O:14])=[N:5]1)([CH3:3])[CH3:2].Cl.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29](O)=O)[CH2:25][CH2:24]1>P(Cl)(Cl)(Cl)=O>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[O:14][C:29]([CH:26]3[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][O:19][CH3:18])[CH2:28][CH2:27]3)=[N:16][N:15]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nc(C(=O)NN)c2ccccc21
Reactant: COCCCN1CCC(C(=O)O)CC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COCCCN1CCC(c2nnc(-c3nn(C(C)C)c4ccccc34)o2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To the mixture of 1-isopropyl-1H-indazole-3-carboxylic acid hydrazide (15.0 grams, 68.8 mmol) and 1-(3-Methoxy propyl)-piperidine-4-carboxylic acid hydrochloride (20.9 grams, 88.2 mmol, obtained in preparation 7) cooled at 0° C. was added phosphoryl chloride (130 mL). The reaction temperature was gradually raised to 100° C. and stirred was 2 hours. Upon completion of the reaction, it was cooled to 0° C. and triturated with hexanes (3×250 mL). The crude product was basified with aqueous sodium hydroxide solution and extracted with 5% methanol in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1-isopropyl-3-{5-[1-(3-methoxy propyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole (15.78 grams)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:29][CH2:28][CH:25]4[CH2:27][CH2:26]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: NCC1CC1
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Preparation 25, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with (cyclopropylmethyl)amine in tetrahydrofuran at room temperature to give 8-chloro-1-[[(cyclopropylmethyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 29 8 -Chloro-1-[[(cyclopropylmethyl)methylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[S-:10][C:11]#[N:12].[K+]>O>[NH:12]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]=2[N:2]=[C:11]1[SH:10]
Reactant: N#C[S-]
Reactant: NC1CCCCC1=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: Sc1nc2c([nH]1)CCCC2
Temperature: 100 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
Dissolve 2-amino-cyclohexanone hydrochloride (2.2 g, 14.7 mmol) and potassium thiocyanate (1.4 g, 14.7 mmol) in water (10 mL). Stir the solution at 100° C. in a sealed flask for 16 h. Cool the mixture and store the mixture at 4° C. for 16 h. Filter off the resulting solid and wash with water (20 mL). Collect the solid, slurry in diethyl ether (20 mL) and filter. Dry the solid in a vacuum oven at 50° C. for 2 h to obtain the title compound as a tan solid (1.4 g, 62%). MS (ES+) m/z: 155.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([CH2:6]Br)=[CH2:5].[CH3:9][NH:10][CH3:11].C1COCC1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:8])[C:4]([CH2:6][N:10]([CH3:11])[CH3:9])=[CH2:5]
Reactant: C=C(CBr)C(=O)OC
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=C(CN(C)C)C(=O)OC
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromomethyl-acrylic acid methyl ester (1 g, 5.59 mmol) in dry CH3CN (20 ml) was added 2M solution of dimethylamine in THF (3.07 ml, 6.14 mmol) followed by K2CO3 (0.93 g, 6.7 mmol). The reaction mixture was stirred overnight, filtered and washed with CH2Cl2. The filtrate was concentrated. The crude product was used in next reaction without further purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C([O-])(O)=O.[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:28](=[NH:29])[C:27]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=2[F:25])[CH:16]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)cc2F)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Anhydrous p-toluene sulfonic acid (25.0 g, 137.43 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (10 g, 55.25 mmol) obtained in step 1 of Preparation Example 1 and 2,4-difluorobenzonitrile (11.53 g, 82.87 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (10.0 g, 31.22 mmol) in a yield of 57%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[CH:15][CH:16]=1
Reactant: OCc1ccc(CCc2ccccn2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To an ethyl acetate (100 mL) solution of 4-(2-pyridin-2-yl-ethyl)benzyl alcohol (3.16 g, 14.8 mmol) described in Manufacturing Example 93-1-4 was added activated manganese dioxide (45 g, 518 mmol), which was stirred for 4 hours at room temperature. The reaction mixture was filtered through a Celite pad, and washed with ethyl acetate (100 mL). The filtrate was concentrated under a reduced pressure to obtain the title compound (2.57 g, 82%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][N:7]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.C(N(CC)CC)C.O>[CH3:18][S:19]([O:1][CH2:2][C:3]1[N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][N:7]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2CO)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccnc2COS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The alcohol described in (b) above (12.6 mg) was dissolved in dichloromethane (2.5 ml) and triethylamine (0.07 ml). This solution was cooled to 0° C. Methanesulfonyl chloride (0.04 ml) was added to the solution dropwise. After stirring for 10 mins the solution was diluted with water and the organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield a white solid which was used in the following reaction without further purification. 1H NMR (250 MHz, CDCl3) d 2.44 (3H, s, ArH), 2.94 (3H, s, SO2CH3), 5.51 (2H, s, CH2SO2), 7.08 (1H, d, J=1.5 Hz, imidazole-H), 7.40 (2H, d, J=8.0 Hz, ArH), 7.49 (1H, d, J=1.5 Hz, imidazole-H), 7.92 (2H, d, J=8.0 Hz, ArH).
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([C:8]2[N:12]3[CH:13]4[CH2:23][CH:15]([C:16]5[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=5[C:11]3=[N:10][C:9]=2[C:24]([NH2:26])=[O:25])[CH2:14]4)[CH2:5]1)(=[O:3])[CH3:2].[C:27]([C:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1)#[CH:28]>>[C:1]([N:4]1[CH2:7][CH:6]([C:8]2[N:12]3[CH:13]4[CH2:23][CH:15]([C:16]5[CH:21]=[CH:20][C:19]([C:28]#[C:27][C:29]6([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]6)=[CH:18][C:17]=5[C:11]3=[N:10][C:9]=2[C:24]([NH2:26])=[O:25])[CH2:14]4)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C#CC1(O)CCCC1
Reactant: CC(=O)N1CC(c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)C1
Product: CC(=O)N1CC(c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(C#CC4(O)CCCC4)cc2-3)C1

Procedure:
Similar to as described in General Procedure E, 3-(1-acetylazetidin-3-yl)-10-bromo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 1-ethynylcyclopentanol to give the titled compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:34])[NH:17][C@@H:18]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]([N:21]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]1)=[O:20])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:11]([O:15][C:16](=[O:34])[NH:17][C@@H:18]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:19](=[O:20])[N:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of dimethyl sulfoxide (4.07 g, 52 mmol) and oxalyl chloride (3.61 g, 28 mmol) were added slowly in that order to dichloromethane (50 ml) at -78° C. (S)-[1-Benzyl-2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (24 mmol) in dichloromethane (30 ml) was added to the above solution via canula, the reaction temperature brought to -30° C. for 0.5 hours, then lowered to -78° C. followed by the addition of triethylamine (118 mmol). The reaction was then warmed to 25° C., diluted with ethyl acetate, washed three times with 1:1 saturated NaHCO3 /brine, the organics dried over MgSO4 and concentrated. The resulting foam was purified by chromatography on silica gel eluted with 30, 40 and 50% ethyl acetate in hexanes to give a light yellow foam (7.5 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:19]([O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C)cc1C(=O)O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
1 g of 5-methylsalicylic acid (6.58 mmol) and 1.83 ml of tri-ethylamine (2 equivalents) were dissolved in 80 ml of ethyl acetate. At 0° C., 0.94 ml of acetyl chloride (2 equivalents) was added dropwise, and the mixture was then stirred at 23° C. for 1 h. The precipitated salts are [sic] filtered off. 100 ml of 1M HCl were added to the filtrate, which was then stirred overnight. A homogeneous solution formed, and it was adjusted to about pH 4 with saturated NaHCO3 solution. It was then extracted with chloroform, and the organic phase was washed with a little water and dried over MgSO4. The solvent was substantially removed, and the crude product was recrystallized from hexane/ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:11]=2[CH:21]=1)=[O:5])[CH3:2].[CH3:22][O:23][CH2:24][C@H]1COC(=O)O1>>[C:15]1([C:13]2[O:14][C:10]3[CH:9]=[CH:8][C:7]([N:6]4[CH2:2][C@H:1]([CH2:22][O:23][CH3:24])[O:3][C:4]4=[O:5])=[CH:21][C:11]=3[CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC[C@H]1COC(=O)O1
Reactant: CCOC(=O)Nc1ccc2oc(-c3ccccc3)cc2c1
Product: COC[C@H]1CN(c2ccc3oc(-c4ccccc4)cc3c2)C(=O)O1

Procedure:
3.1 g (11 mmol) of 5-ethoxycarbonylamino-2-phenylbenzofuran are treated with 4(S)-methoxymethyl-1,3-dioxolan-2-one under the conditions described in step 4 of Example 1. 2.5 g of product are obtained. Melting point: 178.5-179.3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[CH:10][C:9]=2[N+:24]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-].O>CCO.[Fe]>[NH2:24][C:9]1[CH:10]=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[C:15]([F:23])[CH:14]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc([N+](=O)[O-])c2-c2ccc(Br)cc2)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2ncc(N)c2-c2ccc(Br)cc2)cc1F
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-nitro-1H-pyrazole from step 2 (2.5 g, 5.7 mmol), iron powder (1.6 g, 28.4 mmol) and NH4Cl (30 mg, 0.57 mmol) in EtOH:H2O (40 mL: 10 mL) was refluxed for 1 h. After cooled to room temperature, the mixture was filtered by celite and washed with ethyl acetate and the filtrate was concentrated. Water (50 mL) was added to the residual oil and extracted with ethyl acetate (80 mL), dried over MgSO4, and concentrated in vacuo gave the title-compound (1.9 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1NCc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(4-fluorobenzylamino)-3-nitropyridine (1.0 g, 4.05 mmol) and 10% Pd/C (0.3 g) in methanol (50 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 5 hours. The product mixture was filtered through a pad of Celite, and concentrated under vacuum. The residual methanol was removed by co-evaporation with benzene. The resultant N2-(4-Fluorobenzyl)pyridine-2,3-diamine was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[C:5]2=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:7][NH:26][N:25]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: COc1ccc(-c2coc3cc(O)c(Cl)cc3c2=O)cc1OC
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)cc1OC
Yield: 65.1 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(3,4-dimethoxy-phenyl)-7-hydroxy-chromen-4-one (0.2 g, 0.62 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude solid product was columned to give 4-Chloro-6-[4-(3,4-dimethoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.139 g, 65.1%); Rf 0.36 Cf SM 0.56 ethyl acetate/hexane (75/25).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Reactant: Cc1onc(-c2cnccc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2cnccc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 66.1 %

Procedure:
Combine 3-(4-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid (0.50 g, 0.0021 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.63 g, 0.0021 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.40, 0.0021 mol), 1-hydroxy-7-azabenzo-triazole (0.29 g, 0.0021 mol), and N,N-diisopropylethyl amine (1.10 mL, 0.0063 mol), in N,N-dimethylformamide (10 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Wash the combined extracts with water and dry over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane to give 0.67 g (66%) of the desired amide. MS(ES): (M+1)+ 483.2, 485.2 m/z.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[C:12]([O:16][C:17]([NH:19][C@H:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][OH:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C@H:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][O:22][S:8]([CH3:7])(=[O:10])=[O:9])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
11 ml of pyridine and then 6.6 ml of methanesulfonyl chloride were added dropwise, at room temperature, to a solution containing 9.9 g of 2(R)-t-butoxycarbonylamino-2-phenylethanol [prepared as described in step (a) above] dissolved in 120 ml of methylene chloride. This mixture was stirred for 15 hours at room temperature, after which the solvent was removed by distillation. The residue was dissolved in ethyl acetate and water and the ethyl acetate layer was separated. This layer was washed with an aqueous solution of potassium hydrogen sulfate and an aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate, after which the solvent was distilled off. The crystalline residue was collected by filtration and washed with a small amount of diisopropyl ether and cyclohexane to give 12.2 g of the title compound, melting at 108°-109° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)(=[O:3])[NH2:2].C1N=CN(C(N2C=NC=C2)=O)C=1>CN(C)C=O>[C:14]1([C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:12])[NH:2][C:1](=[O:3])[CH2:4][C:5]=3[N:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)Cc1nc(-c2ccccc2)ncc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1Cc2nc(-c3ccccc3)ncc2C(=O)N1
Yield: 59.6 %

Procedure:
A solution of 0.670 g (2.61 mmol) of 4-Carbamoylmethyl-2-phenyl-pyrimidine-5-carboxylic Acid and 0.528 g (3.26 mmol) of CDI in 20 mL of N,N-dimethylformamide is stirred overnight at 25° C. The solvent is evaporated and the residue is washed with Et2O (3×). The insoluble material is boiled with CHCl3, collected, washed with hot CHCl3 and Et2O and dried in vacuo to give 0.372 g (60%) of yellow-orange crystals: mp 216-217.5° C. (dec); 1H NMR (DMSO-d6) δ 8.99 (s, 1H), 8.41 (m, 2H), 7.56 (m, 4H), 5.45 (s, 2H); HRMS (ESI) m/e calcd for C13H9N3O2 240.07645. found 240.07652 (M+H)+1. Analysis for C13H9N3O2.0.25H2O: Calcd: C, 64.05; H, 3.94; N, 17.24. Found: C, 63.67; H, 3.91; N, 17.38.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[CH:27]1[CH2:32][CH2:31][N:30](C(OCC2C=CC=CC=2)=O)[CH2:29][CH2:28]1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[NH:30]1[CH2:31][CH2:32][CH:27]([N:3]2[C:2](=[O:1])[C:6]3=[CH:7][N:8]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][CH:17]=4)[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]3=[N:4]2)[CH2:28][CH2:29]1
Reactant: O=C(OCc1ccccc1)N1CCC(n2nc3c4ccccc4n(Cc4ccc(-n5cccn5)cc4)cc-3c2=O)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylmethyl 4-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)piperidine-1-carboxylate (Example 511, 25 mg, 0.045 mmol) was dissolved in ethyl acetate, treated with palladium(II) hydroxide on carbon (2.5 mg, 0.1 wt equiv), sparged under an atmosphere of hydrogen (1 atm) and stirred for 1 hour at ambient temperature. The mixture was sparged under an atmosphere of nitrogen, filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 80:20; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.83 (1H, s), 8.38-8.36 (1H, m), 7.89 (1H, d, J=2.4 Hz), 7.71 (1H, d, J=1.8 Hz), 7.69 (2H, d, j=8.7 Hz), 7.52-7.43 (3H, m), 7.30-7.26 (3H, m), 6.46 (1H, m), 5.59 (2H, s), 4.61 (1H, m), 3.58-3.50 (2H, m), 3.01-2.96 (2H, m), 2.65-2.57 (2H, m), 2.13-2.05 (2H, m) ppm; low resolution mass spectrometry (ES+) m/z 424.9 [(M+H)+; calculated for C25H25N6O: 425.2].