Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 48.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.034 g (48%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:27]([O:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([CH:44]=1)=[N:42][CH:41]=[CH:40][C:39]=2Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[CH2:27]([O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:26][C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:9]([C:6]5[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=5)=[N:10][N:11]=4)=[CH:25][CH:24]=3)=[CH:40][CH:41]=[N:42]2)=[N:37][CH:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Clc1ccnc2cc(OCc3ccccc3)cnc12
Reactant: Oc1ccc(Nc2nnc(-c3ccc(Cl)cc3)c3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(-c2nnc(Nc3ccc(Oc4ccnc5cc(OCc6ccccc6)cnc45)cc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A pyrex reaction tube was charged with 4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenol hydrochloride (344 mg, 894 μmol), 3-(benzyloxy)-8-chloro-1,5-naphthyridine (220 mg, 813 μmol), cesium carbonate (662 mg, 2032 μmol) and 4.1 mL DMSO. The tube was sealed and the mixture was heated at 100° C. for 4 h. Water was added and the resulting precipitate was filtered, washed with water and dried. The crude material was purified by silica gel chromatography, 90/10/1 DCM/MeOH/NH4OH in DCM to provide N-(4-(7-(benzyloxy)-1,5-naphthyridin-4-yloxy)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine. MS: [M+H]=583.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[N+:16]([O-])=O)(O)=[O:2].[H][H].O>C(O)(=O)C.[C].[Pd]>[O:2]=[C:1]1[CH2:4][C:5]2[C:6](=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=2)[NH:16]1
Reactant: CCOC(=O)c1ccc(CC(=O)O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)C2

Procedure:
4 g (15.8 mmol) of the thus obtained ethyl 4-(carboxymethyl)-3-nitrobenzoate and 0.45 g of 10% palladium-carbon were suspended in 15 mL of acetic acid, and the resulting mixture was stirred at room temperature in a hydrogen gas atmosphere for 23 hours. After completion of the reaction, water was added to the reaction mixture and the mixture was filtered to remove insoluble matter, and the filtrate was subjected to extraction with chloroform. The obtained chloroform layer was evaporated to dryness under reduced pressure, and water was added to the residue. Precipitated ethyl 2-oxoindoline-6-carboxylate was then obtained by filtration.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:14]O>>[F:1][CH:2]([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:14])=[O:8])=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)c1ccc(C(F)F)cc1
Agent: Cl
Product: COC(=O)c1ccc(C(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(difluoromethyl)benzoic acid (5.47 g, 31.8 mmol) in MeOH (100 mL) was treated with concentrated aq HCl (0.5 mL, 6.0 mmol), and the reaction mixture was heated to reflux. After 24 hr the solution was cooled to ambient temperature and concentrated in vacuo. The residue was taken up in Et2O and washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated in vacuo. The result was 5.82 g (98%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.13-8.06 (m, 2H), 7.76-7.69 (m, 2H), 7.14 (t, J=55.5, 1H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[F:22][C:23]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][C:23]=2[F:22])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCc1ccc(F)c(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCc1ccc(F)c(-c2nc(-c3ccccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (2.06 g), 2-fluoro-5-hexylbenzonitrile (1.23 g), anhydrous aluminum chloride (0.88 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.60 g of desired compound (refractive index: 1.5779).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][CH:21]1[NH:26][CH:25]([CH3:27])[CH2:24][N:23]([C:28]([C:30]2[NH:34][C:33]([CH:35]=O)=[C:32]([CH3:37])[CH:31]=2)=[O:29])[CH2:22]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:33]4[NH:34][C:30]([C:28]([N:23]5[CH2:22][CH:21]([CH3:20])[NH:26][CH:25]([CH3:27])[CH2:24]5)=[O:29])=[CH:31][C:32]=4[CH3:37])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CC(C)NC(C)C2)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC(C)NC(C)C2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 93.1 mg (73%) of the title compound as a yellow solid. 1H NMR (360 MHz, DMSO-d6) δ 13.39 (br s, 1H, NH), 11.75 (br s, 1H, NH), 9.23 (br s, 1H), 8.32 (s, 1H), 7.73 (dd, J=2.6 & 6.7 Hz, 1H), 7.41 (m, 1H), 7.33-7.38 (m, 2H), 6.57 (d, J=2 Hz, 1H), 4.22 (m, 2H, CH2), 2.68 (m, 2H, CH2), 2.52 (m, 2H, 2×CH), 2.22 (s, 3H, CH3), 0.99 (d, J=6 Hz, 6H, 2×CH3), 0.98 (s, 3H, CH3). MS 510 [M++1].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]=[O+][O-]>CO.ClCCl>[C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CCC1(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(CC=O)CC1

Procedure:
A solution of 5.7 g (31.3 mmol) of 1-allyl-cyclopropanecarboxylic acid tert-butyl ester in 50 mL methanol and 50 mL dichloromethane under nitrogen was taken to −78° C. where ozone was bubbled in for 1 hour. Nitrogen was bubbled in until the familiar blue color dissipated. Three drops of pyridine followed by 2 mL of dimethyl sulfide were added and the cooling bath removed. After 2 hours the reaction was poured into aqueous saturated ammonium chloride solution, extracted with dichloromethane, dried and concentrated to deliver a quantitative yield of the desired aldehyde as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:25]([O:33][CH:34](Cl)[CH3:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:35][CH2:34][O:33][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13])(=[O:6])=[O:7]
Reactant: CC(Cl)OC(=O)c1ccccc1
Reactant: CC(C)(COS(=O)(=O)CCCCl)C(OCc1ccccc1)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)C(OCc1ccccc1)C(=O)OCCOC(=O)c1ccccc1
Yield: 76.9 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (12) (3.0 g, 7.9 mmol) dissolved in 30 mL of anhydrous toluene was reacted with 4.4 g (23.7 mmol) of 1-chloroethyl benzoate (23) in the presence of 2.6 g (9.5 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 3.2 g of a mixture of the title compound (39a) and (3R/S)-4,4-dimethyl-3-(phenylmethoxy)-3,4,5-trihydrofuran-2-one (2a). MS (ESI) m/z 548.97 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[Cl:9][C:10]1[CH:16]=[C:15](I)[C:13]([NH2:14])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:15][CH:16]=1)[NH:14][C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH:2]2
Reactant: C#Cc1cccnc1
Reactant: Nc1ccc(Cl)cc1I
Product: Clc1ccc2[nH]c(-c3cccnc3)cc2c1

Procedure:
3-Ethynylpyridine and 4-chloro-6-iodoaniline are processed according to the method described in Example 86 to give 5-chloro-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 6.96 (s, 1H), 7.14 (dd, J=8.6, 2.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.54 (dd, J=8.0, 4.9 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 8.25 (dt, J=8.0, 1.9 Hz, 1H), 8.50 (d, J=4.5 Hz, 1H), 9.02 (s, 1H). HRMS (ESI) m/z 229.0522 [(M+H)+ Calcd for C13H10ClN2: 229.0533].
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].ICCCCCI>O.C(COC)OC>[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=S(=O)(Cc1cnccc1Cl)c1ccc(Cl)cc1
Reactant: CCCCCC
Agent: ICCCCCI
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cnccc2Cl)CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.58 ml, 0.913 mmol) was added dropwise to a dimethoxyethane (5 ml) solution of the 4-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (138 mg, 0.457 mmol) obtained in Example 104. At −78° C., the resulting mixture was stirred for 20 minutes and then 1,5-diiodopentane (0.068 ml, 0.457 mmol) was added thereto. The temperature of the reaction mixture was gradually raised to room temperature, at which stirring was performed for 17 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (30 mg, 18%) as a white solid. The resulting solid was washed with ether and then collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1c(F)cccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2c(F)cccc2F)n1
Yield: 38 %

Procedure:
Method 1 was followed using 6-bromopicolinic acid (1.0 equiv.) and 2,6-difluorophenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(2,6-difluorophenyl)picolinic acid in 38% yield. LC/MS=236.0 (M+H), Rt=0.87 min.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[N:23]=[C:22](OC)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1>CS(C)=O>[CH3:12][O:13][C:14]1[N:23]=[C:22]([NH:11][CH2:1][C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1
Reactant: COc1ccc2nc(OC)nc(OC)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CS(C)=O
Product: COc1ccc2nc(OC)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 1 h
Yield: 17.8 %

Procedure:
3.75 g (24.8 mmol) of piperonylamine was added to a solution of 2.00 g (8.26 mmol) of the 2,4,6-trimethoxyquinazoline prepared in Example 88 in dimethyl sulfoxide (15 ml). The obtained mixture was stirred under heating at 150° to 160° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.50 g of the title compound as a pale-yellow crystal. molecular formula; C18H17 N3O4
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.S(Cl)(Cl)=O.Cl.[NH2:25][CH2:26][C:27]([NH2:29])=[O:28]>O>[C:27]([CH2:26][NH:25][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])(=[O:28])[NH2:29]
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Reactant: NCC(N)=O
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: NC(=O)CNC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 25 °C

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (100 mg, 0.43 mmol) (from Example 11) and thionyl chloride (0.2M in DCM, 10 mL) was heated to reflux for 2 hours. The reaction was concentrated, the residue was dissolved in DCM, to it was added glycinamide hydrochloride (242 mg, 2.19 mmol), followed by TEA. The mixture was then stirred at room temperature until the reaction was completed by TLC. The reaction was diluted with water and extracted with DCM. The combined DCM was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:4]([CH3:9])=[N+:5]([O-:15])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncccc1CCl
Solvent: ClC(Cl)Cl
Product: Cc1c(CCl)ccc[n+]1[O-]
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-chloromethyl-2-methylpyridine from Step 2 above (0.50 g; 3.5 mmol) in CHCl3 (40 mL) was added m-chloroperoxybenzoic acid (1.1 g of 55:45 mCPBA:mCBA; 3.5 mmol). After 1.5 h, TLC analysis indicated complete conversion to a lower Rf product. The solution was extracted with equal volumes of saturated aqueous NaHCO3 and water, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH as eluant. 3-Chloromethyl-2-methylpyridine N-oxide was obtained as a solid (TLC: Rf =0.30 (97:3 CH2Cl2 :MeOH); FAB MS m/z 158 (M+ +H)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:30][C:31]1C=[C:39]2[C:34](C(Cl)=C([N+]([O-])=O)C=[N:38]2)=[CH:33][CH:32]=1)C1C=CC=CC=1.NCCCCCO.O(CCN)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:38][CH2:39][CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Agent: NCCCCCO
Agent: NCCOc1ccccc1
Product: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A modification of the general method described in Part A of Example 46 was followed using 6-benzyloxy-4-chloro-3-nitroquinoline (10.5 g, 34 mmol), prepared as described in Parts A-D of Example 57, in lieu of 7-benzyloxy-4-chloro-3-nitroquinoline and 5-amino-1-pentanol (3.5 g, 34 mmol) in lieu of 2-phenoxyethylamine. The reaction was heated at reflux for two hours and then allowed to cool to ambient temperature slowly and stirred overnight. An analysis by TLC indicated the presence of starting material, and additional 5-amino-1-pentanol (0.2 equivalent) was added. The reaction was heated at reflux until the reaction was complete as indicated by TLC. Following the work-up, the crude product was purified by column chromatography on silica gel (eluting with 95:5-dichloromethane:methanol) to provide 5.95 g of 5-{[6-(benzyloxy)-3-nitroquinolin-4-yl]amino}pentan-1-ol as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:23]([NH:25][CH3:26])=[O:24]>>[CH2:27]([C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23](=[O:24])[NH:25][CH3:26])[CH2:29][CH3:30])[CH3:28]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=411.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[NH:13]([C:19]([O:21][CH3:22])=[O:20])[NH:14][C:15](OC)=[O:16]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[NH:13]([C:19]([O:21][CH:22]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:20])[NH:14][C:15]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:16]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)NNC(=O)OC
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CN1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Yield: 38.6 %

Procedure:
The procedure of Example 1 is repeated using 33.9 g of 1,2,2,6,6-pentamethylpiperidin-4-ol, 13.3 g of dimethyl hydrazine-1,2-dicarboxylate and 0.31 g of tetrabutyl titanate to afford 14.8 g of the title compound as a white solid; mp 189°-191° C.
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH2:10])[CH3:3].[NH:11]1[CH2:15][CH2:14][N:13]=[C:12]1S(O)(=O)=O>C(O)C(C)C>[CH2:2]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][C:12]1[NH:13][CH2:14][CH2:15][N:11]=1)[CH3:3]
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: CC[C@@H]1CCCC[C@H]1N
Agent: Cl
Solvent: CC(C)CO
Product: CC[C@@H]1CCCC[C@H]1NC1=NCCN1
Temperature: 125 °C
Yield: 65 %

Procedure:
A mixture of trans-2-ethylcyclohexylamine hydrochloride (0.30 g, 2.36 mmol), imidazoline-2-sulfonic acid (0.704 g, 4.72 mmol) and isobutanol (3 ml) was heated to 125° C. and maintained at that temperature for 2 hours. The mixture was cooled to room temperature, concentrated in vacuo and chromatographed (silica gel, 3:1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 0.253 g (a yield of 65%) of the title compound as a white solid, which was characterized spectroscopically.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].Cl.[NH2:14][CH2:15][CH2:16][SH:17].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[ClH:12].[Cl:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH2:9][NH:14][CH2:15][CH2:16][SH:17]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCS
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)c(CNCCS)c1
Reaction time: 24 h
Yield: 78.8 %

Procedure:
T a slurry of 5-nitro-2-chloro-benzaldehyde (1.5 g, 0.0078 mol), 2-aminoethanethiol hydrochloride (2.73 g, 0.023 mol), sodium cyanoborohydride (0.49 g, 0.0078 mol) in anhydrous methanol (30 mL) was added acetic acid (5 mL) and stirred 24 hrs. The mixture was evaporated and the residue triturated with isopropanol giving 2-(2-chloro-5-nitro-benzylamino)-ethanethiol hydrochloride (0.87 g, 45%) as a white solid. MP: 228-231° C.; 1H-NMR (DMSO-d6) δ 9.76-82 (br, 2H), 8.75 (s, 1H), 8.28-31 (d, 1H), 7.85-90 (d, 1H), 4.40 (s, 2H), 3.15-25 (m, 2H), 2.80-90 (m, 2H); LC/MS (ESI+): 247 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:35]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:39]([CH:35]3[CH2:38][CH2:37][CH2:36]3)(=[O:41])=[O:40])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)C1CCC1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1
Reaction time: 8 h
Yield: 92.2 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. Cyclobutanesulfonyl chloride (0.253 g, 1.637 mmol) was added. The solid immediately dissolved. The mixture was stirred overnight, then it was diluted with DCM and washed with brine (1×50 mL). The organic phase was collected, dried on MgSO4 and the volatiles were evaporated under reduced pressure, yielding the product as a pale yellow solid (731.7 mg, 1.51 mmol, 92%).