Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH2:30])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:2](=[O:4])[CH3:1])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
In a stream of nitrogen and under ice-cooling, 162 mg (1.44 mmol) of potassium t-butoxide was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.04 mmol) of 2-(3-benzyloxybenzamido)benzenesulfonamide produced in Reference Example 1, and the mixture was stirred for 1 hour. This solution was mixed with 121 mg (1.54 mmol) of acetyl chloride and stirred at room temperature for 3 hours. After completion of the reaction, this was neutralized by adding an ammonium chloride aqueous solution and then the solvent was evaporated. The resulting residue was extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 160 mg (yield: 35%) of the title compound.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:18][CH3:19])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])=O)(C)(C)C.[ClH:20]>C(O)C>[ClH:20].[ClH:20].[NH2:8][CH:9]([CH2:18][CH3:19])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Product: CCC(N)C(=O)c1cccnc1

Procedure:
A mixture of 2-(t-butoxycarbonylamino)-1-(3-pyridyl)-1-butanone (20.50 g) and 6N hydrochloric acid (38.8 ml) in ethanol (100 ml) was refluxed for one hour. After cooling, the reaction mixture was concentrated under reduced pressure and the resulting residue was triturated with ethanol-ethylacetate (1:1) to obtain 2-amino-1-(3-pyridyl)-1-butanone dihydrochloride (13.40 g) as pale reddish purple crystalline powder.
Reaction SMILES: [C:1]12([C:11]3[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][C:12]=3[O:19][CH3:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[I-:21].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]12([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][I:21])=[CH:13][C:12]=3[O:19][CH3:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: [I-]
Reactant: COc1cc(CCl)ccc1C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(CI)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To all of the above benzyl chloride in acetone (30 mL) is added sodium iodide (1.70 g., 10.0 mmol, 2.90 equiv.) and potassium carbonate (0.450 g., 10.5 mmol, 3.04 equiv.). The mixture is allowed to stir for 18 hours at room temperature. The solvents are evaporated, and the residue extracted twice with EtOAc. The extracts are washed with water and then brine. The organic phase is dried (MgSO4), and concentrated to afford 4-[1-adamantyl]-3-methoxybenzyl iodide (18b) (1.10 g., 2.88 mmol, 84%): mp=143°-144° C.; 1H NMR (300 MHz, CDCl3) δ 7.25 (d, J=7 Hz, 1H, ArH), 6.95 (d, J=7 Hz, 1H, ArH), 6.85 (s, 1H, ArH), 4.46 (s, 2H, ArCH2I), 3.85 (s, 3H, OCH3), 2.07 (s, 9H, adamantyl), 1.77 (s, 6H, adamantyl) .
Reaction SMILES: CO.Cl.[NH2:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1.N[C:13]([NH2:15])=N>CN(C=O)C.[Pd].Cl[Pd]Cl.C(O)C.CCN(CC)CC>[NH2:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]2[CH:9]=[C:8]([C:13]#[N:15])[CH:7]=[N:6][C:7]=2[N:6]=1
Reactant: N=C(N)N
Reactant: Nc1ccnc(N)n1
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cnc2nc(N)nc(N)c2c1
Yield: 95 %

Procedure:
Referring now to Scheme I, compounds 3 and 4 were prepared by reported procedures, which proved to be readily adaptable to large-scale preparations. The reductive dechlorination Steps to give 5 and 6 were done in DMF--MeOH (N,N-dimethylformamide-methyl alcohol) solution containing 5% Pd on BaCO3. This method differs slightly from the reported conversion of 3 to 5, which was done in DMF using PdCl2 with Et3N (triethylamine) serving as the HCl scavenger. Annelation of the 2,4-diaminopyrimidine moiety by treatment of 5 and 6 with guanidine in refluxing EtOH (ethyl alcohol) followed. 2,4-Diaminopyrido[2,3-d]pyrimidine-6-carbonitrile (7) was obtained in 95% yield; starting 5 was no longer present in the reaction mixture after 24 hours according to TLC. The 5-methyl congener 8 formed less readily. Even after 5 days, some 6 was still present, but the unchanged material was easily removed during isolation of 8 in acceptable (58%) yield. Reductive condensation of 7 with diethyl N-(4-aminobenzoyl)-L-glutamate in 70% AcOH (acetic acid) solution in the presence of Raney Ni was done using a procedure similar to that reported for the reductive amination of the corresponding aldehyde. The procedure was adapted from the reported general method for the preparation of quinazoline (5,8-dideaza) analogues of AMT. The diethyl ester 9 thus formed proved to be identical with the sample previously reported. The reductive condensation was then applied to 8 to give the diethyl ester of the corresponding 5-methyl compound 10. The esters 9 and 10 were then hydrolyzed to give 5-dAMT (11) and 5-Me-5-dAMT (12). The methyl compound 12 was methylated at N10 to give 5-methyl-5-deazamethotrexate (5-Me-5-dMTX, 20).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1.[Mn]([O-])(=O)(=O)=O.[K+].CO>C(#N)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1
Reactant: O=[N+]([O-])c1ccc(CCCC2=NCCN2)nc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCCc2ncc[nH]2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 27.7 %

Procedure:
Compound 132 (400 mg, 1.71 mmol) was first dissolved in acetonitrile (20 mL), with potassium permanganate (952 mg, 5.13 mmol) and alumina (1.2 g) added into the solution in batch. After stirring the resulting mixture at room temperature for 40 min, CH3OH (1 mL) was added to reduce excess oxidant. The mixture was then filtered and the solid material was washed with DCM:CH3OH=10:1. The filtrate was concentrated, and purified with silica gel column chromatography (EtOAc:TEA=1:0.1) to give compound 133 (110 mg, 30%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ9.32-9.37 (m, 1H), 8.37-8.42 (m, 1H), 7.35-7.41 (m, 1H), 6.97 (br s, 2H), 2.98 (t, 2H, J=7.2 Hz), 2.78 (d, 2H, J=7.2 Hz), 2.17-2.26 (m, 2H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26]Cl)=[O:24].[Cl-].[NH4+]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][N:15]1[C:14](=[O:16])[O:13][N:12]=[C:11]1[C:7]1[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(OCCl)c1cccc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.23 g of chloromethyl 3-chlorobenzoate was added, ad the mixture was stirred at 60° C. for 3 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.18 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 3-chlorobenzoate (present compound (32)).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH2:46]O)=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.S([Cl:61])(C1C=CC(C)=CC=1)(=O)=O.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH2:46][Cl:61])=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(CO)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(CCl)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 38.3 %

Procedure:
623 mg of the alcohol of Step F were dissolved in 8 ml of dichloromethane with 834 mg of tosyl chloride and a solution of 534 mg of 4-dimethylamino-pyridine and 5 ml of dichloromethane was introduced over 20 minutes. After 1 hour of stirring, 2.2 ml of N hydrochloric acid were added with stirring and the decanted organic phase was dried and distilled under reduced pressure. The residue was chromatographed on silica and eluted with dichloromethane ethyl acetate (9-1) and crystallized from ether to obtain 245 mg of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-chloromethyl-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH2:18][OH:19])[N:9]=[N:8]1.CCOC(C)=O.Cl>CS(C)=O>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH:18]=[O:19])[N:9]=[N:8]1
Reactant: OCc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve the crude [1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-methanol (3.90 g, 0.0097 mol) in DMSO (30 mL) and add N,N-diispropylethylamine (6.77 mL, 0.039 mol). To this solution add sulfur trioxide pyridine complex (3.09 g, 0.019 mol) in DMSO (30 mL) and stir at RT. After 2 h., add the reaction mixture to EtOAc (150 mL) and 0.5 N HCl (200 mL), and separate the layers. Extract the aqueous layer with EtOAc (50 mL). Combine the organic layers and wash with saturated, aqueous sodium bicarbonate (100 mL) and 1.0 N HCl (100 mL). Dry the organic layer over MgSO4, filter, and concentrate to give the title compound. 1H NMR (500 MHz, DMSO) δ 9.91 (s, 1H), 8.02 (s, 1H), 7.69 (s, 2H), 7.55–7.49 (m, 5H), 5.86 (s, 2H); MS (m/e): 400 (M++1).
Reaction SMILES: CN(C)CCN[C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:30])[C:14]3[N:15]([CH3:29])[C:16]4[CH:17]=[CH:18][C:19]([OH:28])=[C:20]([CH2:25][CH:26]=[CH2:27])[C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].[CH2:32]([O:34]C(C1C2C(=C(C)C3N(C)C4C=CC(OCC=C)=CC=4C=3C=2)C=CN=1)=O)[CH3:33]>ClC1C=CC=CC=1Cl>[CH2:32]([O:34][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:30])[C:14]3[N:15]([CH3:29])[C:16]4[CH:17]=[CH:18][C:19]([OH:28])=[C:20]([CH2:25][CH:26]=[CH2:27])[C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])[CH3:33]
Reactant: C=CCOc1ccc2c(c1)c1cc3c(C(=O)OCC)nccc3c(C)c1n2C
Reactant: C=CCc1c(O)ccc2c1c1cc3c(C(=O)NCCN(C)C)nccc3c(C)c1n2C
Solvent: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2c1c1cc3c(C(=O)OCC)nccc3c(C)c1n2C
Yield: 75 %

Procedure:
1-[(2-Dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-hydroxy-10-allyl-6H-pyrido[4,3-b]carbazole ##STR25## 2 g of 1-ethoxycarbonyl-5,6-dimethyl-9-allyloxy-6H-pyrido[4,3-b]carbazole are dissolved in 80 ml of 1,2-dichlorobenzene, and the solution is refluxed for 10 hours. The mixture is cooled and precipitation is observed. The precipitate is suction-filtered and chromatographed on silica using as eluant first dichloromethane and then a dichloromethane/ethanol mixture. 1.27 g of 1-ethoxycarbonyl-5,6-dimethyl-9-hydroxy-10-allyl-6H-pyrido[4,3-b]carbazole are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][C:3]=1[F:30].[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36].CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[F:30][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[CH:15][N:16]=3)[CH:13]=2)[CH:6]=[CH:7][C:2]=1[N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]
Reactant: Fc1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)ccc1Br
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCCN1c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Temperature: 25 °C

Procedure:
To a solution of 6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline (20 mg, 0.04 mmol) in 1,4-dioxane (1 mL) was added 2-pyrrolidinone (5.7 mg, 0.067 mmol), (1S,2S)-N,N′-dimethylcyclohexane-1,2-diamine (1 mg, 0.009 mmol), copper(I)iodide (0.8 mg, 0.004 mmol), and potassium carbonate (13 mg, 0.095 mmol). The mixture was irradiated at under microwave 150° C. for 1 h. After cooling to RT, the solution was purified by RP-HPLC (pH=10) to afford the desired compound. LCMS: (M+H)+=464.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:16][CH2:15][CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]1=2)=[O:23]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)c2ccc(F)cc2Cl)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.8 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.41 mmol), 2-chloro 4-fluoro benzoic acid (71.8 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55.22 mg, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated by rotary evaporation to obtain 2.93 mg of 2-chloro-4-fluoro-N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)benzamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 0.5 ml). 1H NMR (DMSO) 10.0 (bs, 1H), 8.6 (t, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.1-7.25 (m, 3H), 7.0 (d, 1H), 4.55-4.60 (m, 1H), 4.15-4.35 (m, 4H), 3.70-3.8 (m, 2H), 3.09-3.2 (m, 3H), 2.95 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(C(=O)C(C)(C)C)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Ex 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydro-pyrido[2,3-b]indol-2-one and pivaloyl chloride.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[NH:12][C:11](=[O:19])[C:10](=[O:20])[NH:9]2)=O>C(O)C.Cl>[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[NH:12][C:11](=[O:19])[C:10](=[O:20])[NH:9]2
Reactant: O=C(Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-])C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]

Procedure:
A solution of 41 g (0.13 mol) of 6-trifluoroacetamido-7-nitro-2,3(1H,4H)-quinoxalinedione in 300 ml of ethanol and 700 ml of 3 molar hydrochloric acid was refluxed for 3 hours. The reaction mixture was cooled, and the crude product was filtered off and worked up by conventional methods.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[F:24]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[F:24]
Reactant: OCc1ccc(Cl)c(F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-3-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.21 (2H, s), 5.72 (1H, d, J=1.6 Hz), 7.15 (1H, d, J=8.0 Hz), 7.28 (1H, dd, J=1.6 Hz, J=9.6 Hz), 7.40-7.44 (2H, m), 7.57 (1H, d, J=2.08 Hz), 8.04 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10ClFN4O, 329. Found, 329.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2].C[C:22]([N:24](C)C)=O>C(OCC)(=O)C.[Cl-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:22]#[N:24])[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2nc(C(C)(C)C)sc2c1O

Procedure:
A solution of 4-bromo-2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (100 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium(0)(13 mg, 0.014 mmol), 1,1′-bis(diphenylphosphino) ferrocene (15 mg, 0.028 mmol), zinc dust (2 mg, 0.033 mmol), and zinc cyanide (20 mg, 0.168 mmol) in 0.56 mL of dimethylacetamide was heated at 115° C. for 5 h under a nitrogen atmosphere. The mixture was cooled, diluted with ethyl acetate and saturated aqueous ammonium chloride and filtered through a celite pad. The organic fraction was isolated and washed with brine, dried over anhydrous sodium sulfate, and concentrated to a crude residue. The crude material was purified by column chromatography, eluting the desired product from silica gel with a gradient of 10-60% ethyl acetate in hexanes to give 61 mg of the title compound. MS (ESI−): m/z 304.1 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[F:16][C:17]([F:27])([F:26])[C@H:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[NH2:19]>>[F:27][C:17]([F:16])([F:26])[C@@H:18]([NH:19][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: O=C(N[C@@H](c1cccnc1)C(F)(F)F)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (αS)-α-(trifluoromethyl)-3-pyridinemethanamine (CAN 749839-26-7) as starting materials and isolated (21 mg, 54%) as colorless oil; LC-MS (m/z), 386.0870 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:18])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[CH:10]=[C:6]([CH2:4][OH:3])[N:7]([CH3:18])[N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nn1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cn1nc(-c2ccc(Cl)cc2)cc1CO

Procedure:
In analogy to the procedure described for example 1 a], 5-(4-chloro-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester was reduced with lithium aluminium hydride to give [5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanol as colorless crystals.
Reaction SMILES: C1C2CC3N([O])C(C2)CC1C3.[Br-].[K+].[OH:14][CH2:15][C@H:16]1[O:21][C:20]([CH3:23])([CH3:22])[O:19][C@@H:18]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17]1.Cl[O-].[Na+]>C(Cl)Cl>[CH:15]([C@H:16]1[O:21][C:20]([CH3:23])([CH3:22])[O:19][C@@H:18]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17]1)=[O:14]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Reaction time: 0.25 h

Procedure:
To the −15° C. to −5° C. pre-cooled reaction mixture of AZADO (0.002 g), potassium bromide (0.22 g) and methylene chloride (30 ml) added 5 g of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate. Stirred the reaction mixture for 15 minutes at −15° C. to −5° C. 19 ml of sodium hypochlorite solution was added to the reaction mixture at same temperature. Stirred the reaction mixture for 15 minutes. Quenched the reaction mixture with 10% aqueous sodium thiosulfate solution. 20 ml of water was added and separated the both aqueous and organic layers. Washed the organic layer with water followed by brine solution. Distilled off the solvent completely to get the title compound as a solid.