Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-].[Na+].[Na].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:19]([OH:21])=[O:20])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.IC>CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:19]([O:21][CH3:1])=[O:20])[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[CH:10][CH:11]=1
Reactant: C[O-]
Reactant: O=C1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [Na]
Solvent: CI
Solvent: CO
Product: COC(=O)C1(c2ccc(F)cc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a stirred sodium methoxide solution, previously prepared starting from 1.3 parts of sodium in 160 parts of methanol, are added 13 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarboxylic acid and the whole is stirred and refluxed for 1 hour. After cooling to room temperature, 22.8 parts of iodomethane are added dropwise. Upon completion, the whole is heated to reflux and stirring is continued overnight at reflux temperature. The reaction mixture is evaporated and the residue is taken up in trichloromethane. The organic phase is washed successively with water, a 5% sodium hydroxide solution and again with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 5 parts (36%) of methyl 1-(4-fluorophenyl)-4-oxocyclohexanecarboxylate as an oily residue.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])(C)(C)C.[C:21](O)([C:23](F)(F)F)=O.C(Cl)(=O)CC.C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[CH2:9][N:8]([C:6](=[O:7])[CH2:21][CH3:23])[CH2:11]2)=[CH:17][CH:16]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Yield: 87 %

Procedure:
Using the same procedure as described in 46.4, 3-(4-nitro-phenyl)-azetidine-1-carboxylic acid tert-butyl ester was deprotected with TFA (15 ml) in CH2Cl2 (100 ml) and the resulting amine treated with propionyl chloride (290 μl, 3.31 mmol) and triethylamine (470 μl, 3.37 mmol) in THF (80 ml). Purification of the crude product by flash column chromatography (heptane:ethyl acetate, 1:1) provides the title compound (570 mg, 87% for two steps) as a brown oil.
Reaction SMILES: [CH3:1][NH:2][NH:3][C:4]([C:6]1[S:7][C:8]([Br:11])=[CH:9][CH:10]=1)=[NH:5].[CH:12](O)=O>>[Br:11][C:8]1[S:7][C:6]([C:4]2[N:5]=[CH:1][N:2]([CH3:12])[N:3]=2)=[CH:10][CH:9]=1
Reactant: CNNC(=N)c1ccc(Br)s1
Reactant: O=CO
Product: Cn1cnc(-c2ccc(Br)s2)n1

Procedure:
A mixture of compound 5-bromo-thiophene 2-carboximidic-N′-methyl-hydrazide (4BW) (13 g) in formic acid (100 ml) was refluxed overnight and concentrated. The residue was treated with sat. NaHCO3, and extracted with EtOAc three times. The combined organics were dried over MgSO4. After concentration, compound 5BW was purified by column using 80% EtoAc/hexane to yield light yellow colored solid.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([O:17][C:18]1[C:19]([C:24]([CH3:28])([CH3:27])[C:25]#N)=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:12]2.C(=O)([O-])[OH:30].[Na+].[CH2:34]([OH:36])[CH3:35]>>[CH2:34]([O:36][C:25](=[O:30])[C:24]([C:19]1[C:18]([O:17][C:13]2[CH:14]=[N:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[F:6])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:27])[CH3:28])[CH3:35]
Reactant: O=C([O-])O
Reactant: CCO
Reactant: CC(C)(C#N)c1ncccc1Oc1cnc2c(F)cccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1ncccc1Oc1cnc2c(F)cccc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
2 ml of ethanol and 2 ml of concentrated sulfuric acid were added to 0.38 g of 2-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-2-methylpropionitrile. The mixture was stirred for 6 hours at 100° C. Subsequently, saturated aqueous sodium hydrogen carbonate solution was added thereto to stop the reaction. The resultant was then extracted with ethyl acetate followed by distilling off the solvent of the organic layer. Subsequently, the resultant was purified by silica gel column chromatography to obtain 0.24 g of 2-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-2-methylpropionic acid ethyl ester.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.N1C=CC=CC=1>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
To a stirred solution 4-nitrophenyl chloroformate (26.0 mg, 0.13 mmol) in anhydrous CH2Cl2 was added a solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (27.0 mg, 0.13 mmol) and pyridine (7 μL) in CH2Cl2 (0.5 mL). The mixture was stirred for 30 min. LC-MS showed complete conversion. This intermediate was used as a solution for the next step.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.ClCCC[N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc2c(c1)oc(=O)n2N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2CO3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2.3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31%) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-6-acetyl-2-benzoxazolinone, m.p.=152°-154° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:13][C:4]1[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=1[NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11]
Reactant: C[C@@H](CO)Nc1cnc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H](CO)Nc1cnc(Br)cc1N
Temperature: 80 °C
Yield: 62.9 %

Procedure:
Iron powder (0.101 g, 1.811 mmol) was added to a solution of (S)-2-(6-bromo-4-nitropyridin-3-ylamino)propane-1-ol (0.050 g, 0.181 mmol) and ammonium chloride (2.422 mg, 0.045 mmol) in ethanol (2.0 mL) and water (0.7 mL). The reaction mixture was heated at 80° C. for 2 h. The mixture was cooled to room temperature and filtered through celite (washing with methanol). The filtrate was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford (S)-2-(4-amino-6-bromopyridin-3-ylamino)propane-1-ol (0.028 g, 63%) as a purple solid. MS (ESI, pos. ion) m/z 246, 248.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31].C(N(C(C)C)C(C)C)C>C(O)CC>[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1
Reactant: NCc1cccc(O)c1
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: Oc1cccc(CNc2ncnc3c2ncn3C2CCCO2)c1
Yield: 85 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)-purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) of 3-hydroxybenzylamine, and 5 ml of N-ethyldiisopropylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 85%, white solid. TLC (EtOAc:hexane (1:1 (v:v)): single spot; HPLC: purity>98%. 1H NMR (400 MHZ, DMSO): 2.20sep (1H, J=6.8 Hz); 2.22sep (1H, J=6.8 Hz); 2.44m (2H); 3.91 q (1H, J=7.3 Hz); 4.14q (1H, J=7.3 Hz); 4.63bs (2H); 6.26m (1H); 6.59dd (1H, Ja=7.8 Hz, Jb=2.2 Hz); 6.73s (1H); 6.75d (1H, J=7.8 Hz); 7.07t (1H, J=7.8 Hz); 8.20s (1H); 8.26bs (1H); 8.27s (1H); 9.23bs (1H). MS (ES): [M+H]+=312 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([CH:26]4[CH2:28][CH2:27]4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:21]([C:19]2[C:18]([CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:11]3[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:20]=2)[S:22]([CH3:25])(=[O:23])=[O:24])[CH:33]=[CH:32][C:31]=1[N+:37]([O-:39])=[O:38]
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (2.00 g, 4.77 mmol), 2-chloro-4-fluoronitrobenzene (1.68 g, 9.55 mmol), and potassium carbonate (1.98 g, 14.3 mmol) in 4:1 DME/water (20 mL) in a sealed vessel was heated to 100° C. with stirring. After 18 hours the mixture was treated with an additional 2.00 g portion of potassium carbonate, heated at 100° C. for another 15 hours, and then stirred at RT for 3 days. The mixture was partitioned between EtOAc and water. After separating the phases, the aqueous portion was extracted with two additional portions of EtOAc. The combined EtOAc solutions were washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 7:3 DCM/EtOAc) to afford a tacky, yellow foam. This material was crystallized from hexane/EtOAc to give the title compound (1.78 g, 65%) as a light yellow solid. LCMS (m/z, ES+)=574 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=O)[CH2:4][CH2:3]1.[CH3:16][Li].[Cl-].[NH4+]>CCOCC>[CH3:15][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](=[O:14])[CH3:16])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C(=O)O)c2ccccc21
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)C1CCC(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
16.8 g of 1,1-dimethyl-tetralin-4-carboxylic acid are treated dropwise in 200 ml of absolute ether under a nitrogen or argon atmosphere with 99.2 ml of a 2 molar solution of methyl lithium in ether (198.4 mmol). The mixture is stirred at room temperature for 1 hour and subsequently held at reflux temperature for a further 1 hour. The mixture is poured into saturated ammonium chloride solution, extracted with ether, washed neutral with water and dried over sodium sulphate. The ether is evaporated and the residue is fractionally distilled. There are obtained 8.4 g of 1,1-dimethyl-4-acetyl-tetralin of boiling point 69° C./0.07 mmHg; nD20 =1.5333; yield 50%. Odour: see (5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O.[NH2:23][OH:24].Cl.C([O-])(=O)C.[NH4+]>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[N:23][OH:24]
Reactant: NO
Reactant: O=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To the compound (2,4-difluorophenyl)[l-(phenylmethyl)-3-pyrrolidinyl]methanone (22 g) in 95% ethanol (350 ml) and water (100 ml) was added NH2OH.HCl (10.1 g) and ammonium acetate (12.7 g, 2.1 eq). The resulting mixture was refluxed for 3.5 hours. The mixture was then allowed to stir at room temperature for 24 hours. The reaction mixture was concentrated to remove ethanol, poured into water (500 ml), and extracted with dichloromethane (500 ml). This was followed by washing with water, brine, and drying over magnesium sulfate. The product was concentrated to an oil and purified by column chromatography to yield 12 g of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime.
Reaction SMILES: Cl[C:2]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:5]([C:6]([NH:8][CH2:9][C@@H:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[CH2:14][CH2:13]2)=[O:7])=[CH:4][N:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[O:18][CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C@H:10]([OH:27])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[C:28]([C:30]([F:32])([F:31])[F:33])=[CH:29][C:2]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[N:3][CH:4]=2)[CH2:13][CH2:14]1
Reactant: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1cnc(Cl)cc1C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)cn1
Yield: 8 %

Procedure:
A stirred solution of 6-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-(trifluoromethyl)nicotinamide (0.28 g), methanesulfonamide (0.12 g) and potassium carbonate (0.148 g) in N-methyl-2-pyrrolidinone was heated under microwave irradiation (100 W) at 100° C. for 15 min. The reaction mixture was concentrated in vacuo and redissolved in 4:1:1 acetonitrile/water/acetic acid (6 mL) and subjected to RPHPLC (gradient 0.1% ammonium acetate/acetonitrile 95% to 5%) to yield a white solid (0.025 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[NH2:3].[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH:24][C:25](=[O:38])/[C:26](/[C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=O)=[CH:27]\N(C)C)[CH2:21]2>C(O)C.C(O)(=O)C>[CH:16]12[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:14]([CH2:23]3)[CH:15]1[NH:24][C:25]([C:26]1[CH:27]=[N:3][N:2]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)[C:31]=1[CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:38])[CH2:22]2
Reactant: CN(C)/C=C(\C(=O)NC1C2CC3CC(C2)CC1C3)C(=O)C1CCCC1
Reactant: COC(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C2CCCC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
Methyl 4-hydrazinylbenzoate hydrochloride (Intermediate #123) (0.712 g, 3.51 mmol) was added in one portion to (Z)—N-(2-adamantyl)-2-(cyclopentanecarbonyl)-3-dimethylamino-prop-2-enamide (Intermediate #67), 1.21 g, 3.51 mmol) in ethanol (30 mL). 5 drops of acetic acid were added and the resulting solution was stirred at 80° C. for 2 hours and then cooled to ambient giving a precipitate. The reaction mixture was filtered and the product recovered, washed with ethanol (10 mL) and water (10 mL) before being dried under vacuum to give methyl 4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoate (0.620 g, 39.4%) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[C@@H:4]([CH3:8])[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:30][NH:31][CH3:32].C(N(CC)CC)C.Cl>ClCCl>[CH2:1]([C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[C@@H:4]([CH3:8])[C:5]([N:31]([CH3:32])[CH3:30])=[O:6])[CH3:2]
Reactant: CNC
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)C(=O)N(C)C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
The product of Example 4 (3 g, 10 mmol) was dissolved in dichloromethane (10 ml), oxalyl chloride (2.6 ml, 30 mmol) was added dropwise, and it was reacted at room temperature for 1 hr, then the reaction solution was concentrated to give a pale yellow oil which was further dissolved in dichloromethane. And then the resulted solution was added dropwise to an ice-water bath cooled solution of dimethylamine hydrochloride (1.6 g, 20 mmol) and triethylamine (4.3 ml, 30 mmol) in dichloromethane, then the mixture was slowly warmed to room temperature to react for 1 hour. The pH thereof was adjusted to about 7 with 1N hydrochloric acid, then it was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated and recrystallized with petroleum ether and ethyl acetate to give a white solid 3.1 g, yield: 95%. 1HNMR (300 MHz, CDCl3): δ 7.3-7.5 (5H, m), 7.2 (1H, m), 6.7-6.8 (3H, m), 5.0 (2H, s), 2.8-2.9 (1H, m), 2.7-2.8 (1H, m), 2.6 (3H, s), 2.5 (3H, s), 1.8-1.9 (1H, m), 1.4-1.6 (1H, m), 1.1 (3H, d, J=6.2), 0.8 (3H, t, J=6.8, 14.1). ESI-MS: 326.4 (M+H).
Reaction SMILES: [Cl:1][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[CH:18]1([NH2:21])[CH2:20][CH2:19]1.[Na+].[I-]>CO>[ClH:1].[CH:18]1([NH:21][CH:2]([CH3:17])[C:3]([C:5]2[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=23)=[O:4])[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(NC1CC1)C(=O)c1c(C(C)C)nn2ccccc12
Product: Cl
Yield: 54.8 %

Procedure:
621 mg (2.4 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one was reacted with 283 mg (4.8 mmol) cyclopropylamine in the presence of 20 mg of NaI in 6 ml of MeOH. The crude product obtained after workup was acidified with 2N HCl-ether to furnish 405 mg of 2-(cyclopropylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one hydrochloride. Compound 1045.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8].Br[CH2:14][CH2:15][CH2:16][Cl:17]>CN(C=O)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[OH:3]
Reactant: N#Cc1ccc(O)c(O)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCCl)c(O)c1
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
NaH (0.20 g; 8.14 mmol) was added to a room temperature solution of 3,4-dihydroxybenzonitrile (1.00 g; 7.40 mmol) in DMF. After stirring for 15 minutes, 1-bromo-3-chloropropane (1.3 g; 8.14 mmol) was added to the mixture. The reaction was stirred for 40 h at room temperature, and then quenched with water and extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (4×100 mL), dried over Na2SO4 and concentrated in vacuo. The resulting crude product was chromatographed on a column of silica (5 cm×18 cm) eluting with a mixture of EtOAc and hexanes (1:4). Fractions containing the desired product were combined and concentrated in vacuo to afford the sub-title compound as an oil (0.5 g; 32%).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:29][NH2:30].Cl>ClCCl.CN(C)C=O>[OH:29][NH:30][C:17](=[O:18])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:11]=1
Reactant: C[Si](C)(C)ON
Reactant: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1
Reaction time: 1.5 h
Yield: 20.6 %

Procedure:
0.231 g of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound A1) are dissolved in 8 ml of dichloromethane at room temperature. Then 50 μl of N,N-dimethylformamide (DMF) are added, 0.275 g of oxalic acid chloride dissolved in 2 ml of dichloromethane are added dropwise and stirred for 1.5 hour. To the solution are added 0.439 g of O-(trimethylsilyl)hydroxylamine and stirred for 15 minutes. Then 20 ml of aqueous hydrochloric acid (1 M strength) are added and extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate. Afterwards it is filtered and evaporated under vacuo. The crude product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol from 98:2 to 6:4 to yield 0.050 g of the title compound as a white solid.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=O)=CC=1)([O-])=O.O.[NH2:20][NH2:21]>CO>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[NH:11][C:9](=[O:8])[NH:20][NH2:21]
Reactant: NN
Reactant: O=C(Nc1nccs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CO
Product: NNC(=O)Nc1nccs1

Procedure:
A solution of 2-(4-nitrophenoxycarbonyl)aminothiazole, 3.5 g (13 mMole) and 85% hydrazine hydrate, 4.0 ml (69 mMole) in 40 ml of methanol was stirred under nitrogen at 22° C. for 10 days. The mixture was cooled in ice. The insolubles were filtered, washed with cold methanol, dried and recrystallized from ethanol furnishing 780 mg of (thiazol-2-yl)semicarbazide, m.p. 166°-167° C., which was characterized by nuclear magnetic resonance, mass spectra, infrared spectra and elemental analyses.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1
Reactant: COC(=O)C[C@H]1CCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CCCN1c1nc(Cl)ncc1N

Procedure:
A mixture of 3.3 g (0.011 mole) of [(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (IV-102) in 150 mL of ethyl acetate and 0.8 g of 10% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. The filtrate was concentrated under reduced pressure to give [(R)-1-(5-amino-2-chloro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (V-102), which also contained a small amount of (R)-9-chloro-2,3,3a,4-tetrahydro-1H,6H-6,8,10,10b-tetraaza-benzo[e]azulen-5-one. This material was used directly in the next step without further purification.