Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]2[C:28](=[O:29])[N:27]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33](=[O:37])[N:32]([CH3:38])[CH:31]=3)[CH:26]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[C:10]=2[N:11]([CH:23]([CH3:25])[CH3:24])[C:12]=1[C:13]1[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:7])C>C1COCC1.CO>[Cl:36][C:34]1[C:33](=[O:37])[N:32]([CH3:38])[CH:31]=[C:30]([N:27]2[C:28](=[O:29])[C:9]3[C:8]([C:6]([OH:7])=[O:5])=[C:12]([C:13]4[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=4)[N:11]([CH:23]([CH3:25])[CH3:24])[C:10]=3[CH:26]2[C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH:35]=1
Reactant: CCOC(=O)c1c2c(n(C(C)C)c1-c1cnc(OC)nc1OC)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncc(-c2c(C(=O)O)c3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2N Aqueous NaOH (0.208 mmol) was added to a solution of 5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrole-3-carboxylic acid ethyl ester (Example 220) (0.104 mmol) in 1:1 THF/MeOH (2 mL) and the mixture was stirred at 80° C. for 1 h. After evaporation of MeOH, the pH was adjusted to 5 with addition of 10% w/w aqueous citric acid and extracted with EtOAc (3×). The combined organic phases were successively washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by SFC to afford the title compound as a white solid. tR: 1.10 min (HPLC 3); ESI-MS: tR=0.97 min, [M+H]+ 598/600/602 (LC-MS 1); TLC: Rf=0.31 (9:1 CH2Cl2/MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[H-].[Na+].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13].[NH4+].[Cl-]>CS(C)=O>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH3:13]
Reactant: N#Cc1cccc(N)c1
Reactant: CCOC(CBr)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(CNc1cccc(C#N)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
To a stirred solution of 3-aminobenzonitrile (2.50 g, 21.10 mmol) in anhydrous DMSO (30 mL) at 0° C. was added NaH (0.61 g, 25.39 mmol) portionwise, and the mixture was stirred at room temperature for 20 min and then treated with bromoacetaldehyde diethyl acetal (4.20 g, 21.10 mmol). After 2 h, to it, saturated aqueous NH4Cl (20 mL) was added slowly at 0° C., and the reaction mixture was extracted with EtOAc (2×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using EtOAc and hexane as eluent to give 3-(2,2-diethoxyethylamino)benzonitrile (0.86 g, 17%) as a light orange oil. 1H NMR (400 MHz, CDCl3): δ 7.22 (td, 1H, J=7.8, 0.6 Hz), 6.97 (m, 1H), 6.84-6.81 (m, 2H), 4.67 (t, 1H, J=5.4 Hz), 3.77-3.69 (m, 2H), 3.61-3.53 (m, 2H), 3.24 (d, 2H, J=5.6 Hz), 1.24 (t, 6H, J=7.0 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][F:38])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.ClCCl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:40]=[CH:39][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][F:38])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:41][CH3:42])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCN(CCF)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(CCF)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A mixture of 0.08 g (0.25 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.075 g (0.25 mmole) of 4-amino-N-[1-(2-fluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide and 0.072 g (0.38 mmole) of p-toluenesulfonic acid monohydrate in 3 mL of isopropanol was stirred in a sealed tube at 140 degrees overnight. The mixture was cooled, and dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.080 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(2-fluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide (I-75).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[NH2:9][CH2:10][CH2:11][OH:12]>CCO>[C:1]([CH2:3][C:4]([NH:9][CH2:10][CH2:11][OH:12])=[O:6])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: NCCO
Solvent: CCO
Product: N#CCC(=O)NCCO
Yield: 90.6 %

Procedure:
To a solution of ethyl 2-cyanoacetate (10 g, 9.41 mL, 88 mmol) in EtOH (100 mL) was added 2-aminoethanol (5.40 g, 5.34 mL, 88 mmol). The mixture was refluxed for 4 h before concentration in vacuo. The mixture was purified on a 100 g Silica column eluting with 0-10% MeOH/DCM. Desired fractions were collected and concentrated to yield the desired product as a brown oil (10.2 g, 79.7 mmol, 90%). The sample was used directly in the next step without any further purification.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=O.Cl.[NH2:24][OH:25].[OH-].[Na+].O>CO>[N:24](=[C:14]1[CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]34[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]2[CH2:20][C:7]2[CH:8]=[CH:9][C:10]([OH:22])=[C:11]([O:12][C@@H:13]13)[C:6]4=2)[OH:25]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=NO)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of oxymorphone (1.2 g, 4 mmol) and hydroxylamine hydrochloride (0.35 g, 5 mmol) in 20 mL of methanol was treated with 2 mL of 10% aqueous NaOH and stirred at room temperature for 15 h. The reaction mixture was poured into water and extracted with 150 mL CHCl3 (3×50 mL). The CHCl3 extract was dried (MgSO4), and evaporated. The residue was recrystallized from THF-petroleum ether yielding 600 mg (47.4%), mp 270-71 C. IR: (KBr): No C=O absorption at 1720 cm-1. 1H NMR (d6DMSO) δ 4.83 (s, C5H), Rf: silica gel EtOAc-EtOH-NH40H (100:1:1) 0.18. Anal. Calcd for C17H20N2O4 :C, 64.54; H, 6.37; N, 8.86. Found C, 64.76; H, 6.5; N, 8.58.
Reaction SMILES: [F:1][CH:2]([F:11])[CH:3]([NH2:10])[CH2:4][C:5]([O:7]CC)=[O:6].[ClH:12]>>[ClH:12].[F:1][CH:2]([F:11])[CH:3]([NH2:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(N)C(F)F
Agent: Cl
Product: NC(CC(=O)O)C(F)F
Temperature: 100 °C
Yield: 80 %

Procedure:
Ethyl 4,4-difluoro-3-amino-butanoate prepared as in Step B (3.340 g, 20 mM) is dissolved in 1 M HCl (20 ml) and the mixture heated at 100° C. for 3 hours. The solvent is evaporated in vacuo. The oily residue is crystallized from ethanol/ether; 2.800 g of 4,4-difluoro-3-amino-butanoic acid, hydrochloride (yield 80%). Mp: 150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6](Cl)=[O:7])[CH2:5][CH2:4]1.Cl.[CH3:10][NH:11][O:12][CH3:13].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1([O:2][CH3:1])[CH2:5][CH2:4]1)=[O:7]
Reactant: CNOC
Reactant: COC1(C(=O)Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C1(OC)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
10 g (74 mmol) of 1-methoxy-cyclopropane-carbonyl chloride are added at 20° C. with stirring to a mixture of 8 g (82 mmol) of N,O-dimethyl-hydroxylamine hydrochloride and 100 ml of absolute dichloromethane. 13 g (164 mmol) of absolute pyridine are then added dropwise at 0° C. The mixture is initially subsequently stirred at 20° C. for one hour and then at 40° C. for one hour, the precipitate is then filtered off and 100 ml of dichloromethane are added. The reaction mixture is washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. The remaining residue is subjected to a vacuum distillation. 10 g (85% of theory) of N-methoxy-N-methyl-1-methoxy-cyclopropanecarboxamide are obtained in this manner in the form of an oil having a boiling point of b.p.=125° C. at 20 mbar. ##STR35##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:26][O:27][C:28]([C:30]1[CH:31]=[N:32][C:33](Cl)=[N:34][CH:35]=1)=[O:29].N12CCN(CC1)CC2>C(N(CC)CC)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[N:32][C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[N:34][CH:35]=1)=[O:29]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: COC(=O)c1cnc(Cl)nc1
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
In analogy to Example 163, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with methyl-2-chloropyrimidine-5-carboxylate in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as a colorless solid. MS (m/e)=512.2 [M+H+].
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[N:23][CH:24]=1>>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:31](=[O:32])[C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][N:23]=5)=[CH:30][CH:29]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)nc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4nc(C5CC5)c(C)n4c3)cc2)nc1

Procedure:
Operations similar to Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(5-methoxy-2-pyridyl)benzenecarboxylic acid, to provide the title compound as white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3]([O:6][C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=[O:5])=[O:4].[Cl:28]N1C(=O)CCC1=O.O>CN(C=O)C>[F:27][C:2]([F:26])([F:1])[S:3]([O:6][C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[C:15]([Cl:28])[C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=[O:5])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Temperature: 50 °C
Yield: 47.8 %

Procedure:
To a solution (10 mL) of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (500 mg) obtained in Step C of Example 35 in DMF was added N-chlorosuccinimide (215 mg) at room temperature. The reaction mixture was heated at 50° C. for 21 hr, and the mixture was allowed to be cooled to room temperature. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (259 mg).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:6][CH2:5]1)[CH3:3].[BH4-].[Na+]>C1COCC1.CO>[CH3:3][CH:2]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: COc1cc(N2CCCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCCN(C(C)C)CC2)ccc1N
Yield: 71.9 %

Procedure:
1-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (0.565 g, 1.92 mmol) was suspended in 5 mL THF and 10 mL MeOH. NiCl2-6H2O (138 mg, 0.576 mmol) was added followed by slow addition of NaBH4 (218 mg, 5.76 mmol). The reaction mixture was adsorbed on SiO2 and purified via column chromatography to afford 4-[4-(1-methylethyl)hexahydro-1H-1,4-diazepin-1-yl]-2-(methyloxy)aniline (364 mg, 1.38 mmol). 1H NMR (400 MHz, DMSO-d6)δ ppm 0.89-1.06 (m, 6 H) 1.71-1.88 (m, 2 H) 2.69 (br. s., 2 H) 2.81-2.97 (m, 1 H) 3.23-3.47 (m, 6H) 3.66-3.77 (m, 3 H) 3.82-4.27 (m, 2 H) 6.08 (br. s., 1 H) 6.25 (br. s., 1 H) 6.49 (br. s., 1 H). ESIMS (M+H)+=264.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31](B4OC(C)(C)C(C)(C)O4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1>>[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:19]4[C:16]5[CH:17]=[N:18][C:13]([C:3]6[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=6[Cl:12])=[CH:14][C:15]=5[NH:21][N:20]=4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C4CC4)C5=O)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (Example 21, Step 2). LCMS (M+H)+=495.1/497.1.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:17]([CH3:38])[O:16][C@H:11]1[O:12][CH2:13][CH:14]=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:43]CC1>CC(C)=O.O.O=[Os](=O)(=O)=O>[C:1]([O:9][C@H:10]1[C@H:19]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:18]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:17]([CH3:38])[O:16][C@H:11]1[O:12][CH2:13][CH:14]=[O:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1O[C@@H](OCC=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of prop-2-en-1-yl 2,3,4-tri-O-benzoyl-α-L-fucopyranoside (6.06 g, 11.73 mmol) in acetone (94 mL) and water (23.5 mL) was added 4-methylmorpholine 4-oxide (2.75 g, 23.46 mmol) followed by the addition of 2.5% OsO4 in water (5.97 g, 0.587 mmol). The mixture was allowed to stir at rt for 16 hr. To the resulting mixture was then added a solution of NaIO4 (5.40 g, 23.46 mmol) in water (100 mL). After stirring for additional 6 hr, the precipitate was filtered and washed with acetone (200 mL). The volume of the filtrate was reduced to approximately ⅓ of the initial volume and then extracted with EtOAc (200 mL). The organic phase was separated, washed with sat. NaHCO3 (200 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The organic phases were combined and washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (220 g), eluting with 0-100% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3) δ 1.33-1.29 (3H, m), 3.27 (1H, s), 3.41 (1H, s), 4.35-4.31 (1H, m), 5.51-5.45 (1H, m), 5.75-5.69 (1H, m), 5.81 (1H, dd, J=13.91, 3.57), 6.05-5.98 (1H, m), 7.42 (2H, d, J=7.76), 7.53 (5H, d, J=8.61), 7.67-7.63 (2H, m), 7.84-7.81 (2H, m), 8.01 (2H, t, J=8.82), 8.14-8.12 (2H, m), 9.77-9.77 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH2:11])[CH:6]=[C:5]2[CH3:12].[CH3:13][C:14]1[C:19]([C:20](O)=[O:21])=[CH:18][N:17]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:15]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:20]([C:19]1[C:14]([CH3:13])=[N:15][C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:17][CH:18]=1)=[O:21])[CH:6]=[C:5]2[CH3:12]
Reactant: Cc1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.5 %

Procedure:
5-Fluoro-3-methyl-indol-1-ylamine (10.6 mmol) is treated with 4-methyl-2-pyridin-2-ylpyrimidine-5-carboxylic acid (2.75 g, 12.8 mmol) in DMF (75 mL) and the mixture is stirred at rt for 10 min. The mixture is then treated with 2,4-dimethoxy-6-(4-methylmorpholin-4-yl)-[1,3,5]triazine chloride (3.82 g, 13.85 mmol) and stirred at 60° C. for 1 h. The mixture is concentrated in vacuo. The residue is diluted with Et2O (50 mL) and 10% NaHCO3 (50 mL), and the mixture is stirred at rt for 20 min. The resulting solid is filtered, washed, and dried to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)amide (3.2 g, 83%). The solid is crystallized with MeOH:water (4:1) to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)amide as a crystal. MS: 362 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.27 (s, 3H), 2.78 (s, 3H), 7.06 (m, 1H), 7.34 (m, 1H), 7.37 (s, 1H), 7.44 (m, 1H), 7.59 (m, 1H), 8.05 (m, 1H), 8.45 (m, 1H), 8.80 (m, 1H), 9.25 (s, 1H). IC50=7 nM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][C:10]([CH3:12])=O>>[CH2:12]([N:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[N:6][C:5]1=[O:8])[CH:10]=[CH2:9]
Reactant: O=c1ncc(Br)c[nH]1
Reactant: CC(C)=O
Product: C=CCn1cc(Br)cnc1=O
Yield: 40 %

Procedure:
1-Allyl-5-bromopyrimid-2-one was prepared from 5-bromopyrimid-2-one as above in 40% yield m.p. 142°-143° C. (acetone)
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[O:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:6][NH:5][CH2:4]1.Cl[C:18]1[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:2][C:3]1([CH3:16])[O:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:6][N:5]([C:18]2[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)[N:19]=2)[CH2:4]1
Reactant: CC1(C)CNCC(c2ccc(F)cc2)O1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(N2CC(c3ccc(F)cc3)OC(C)(C)C2)nc(-c2ccncc2)cc1=O
Yield: 85.7 %

Procedure:
A solution of 2,2-dimethyl-6-(4-fluorophenyl)morpholine hydrochloride (127 mg, 0.517 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (109 mg, 0.491 mmol) and triethylamine (0.180 ml, 1.29 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (166 mg, 81%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([C:26](O)=[O:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([NH2:34])([CH3:33])([CH3:32])[CH3:31].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:30]([NH:34][C:26]([C:24]1[CH:25]=[C:20]2[CH:19]=[C:18]([CH:7]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[NH:29][C:21]2=[N:22][CH:23]=1)=[O:27])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Reaction time: 14 h
Yield: 103.2 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (prepared as in Example 3, 240 mg, 0.58 mmol) and tert-butylamine (122 μL, 1.16 mmol) in dichloromethane (4 mL), N,N-dimethylformamide (500 μL) and N-methylmorpholine (160 μL, 1.55 mmol) was added 1-hydroxybenzotriazole hydrate (132 mg, 0.97 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (186 mg, 0.97 mmol) in one portion at room temperature. The resulting mixture was stirred for 14 h. The mixture was diluted with ethyl acetate (100 mL), washed with a 1N aqueous sodium bicarbonate solution, 1 N aqueous hydrochloric acid solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid tert-butylamide (280 mg, quant.) as a light yellow solid which was used without further purification: LC/MS m/e calcd for C26H33N3O3S [M+H]+ 468.64, observed 467.8.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:3]1=[O:25].Cl[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[CH:28]1([CH2:27][N:7]2[C:6]3[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:3](=[O:25])[N:2]([CH3:1])[C:10]=3[N:9]=[CH:8]2)[CH2:30][CH2:29]1
Reactant: ClCC1CC1
Reactant: CCOP(=O)(CCCCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Product: CCOP(=O)(CCCCCn1c(=O)c2c(ncn2CC2CC2)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.011 mol of diethyl [5-(3-methyl-xanthin-1-yl)pentyl]phosphonate and 0.013 mol of chloromethylcyclo-propane analogously to Example 46.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([O:33][CH3:34])[CH:26]=1)[NH2:24].O1CCCC1>CO>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[O:33][CH3:34])#[N:30]
Reactant: COc1cc(NN)ccc1C#N
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)ccc1C#N
Yield: 49 %

Procedure:
The title compound was prepared from Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (310 mg, 1.09 mmol) and 4-hydrazinyl-2-methoxybenzonitrile hydrochloride; Preparation 4 (282 mg, 1.42 mmol) according to Method B (methanol was used in place of ethanol as solvent) and Method C. The crude precipitate was purified by reverse phase chromatography with 40-95% acetonitrile/water to give the title compound (yellow solid, 220 mg, 0.53 mmol, 49% yield). The title compound was largely present as (±)-(3SR,3aRS)-2-(4-cyano-3-methoxyphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (m, 7H), 1.65-1.90 (m, 2H), 1.99-2.12 (m, 1H), 2.18-2.27 (m, 1H), 2.82-2.95 (m, 1H), 3.04-3.13 (m, 1H), 3.52-3.63 (m, 1H), 3.90 (s, 3H), 4.94 (dd, J=9.67, 5.37 Hz, 1H), 6.80 (dd, J=8.59, 1.88 Hz, 1H), 6.90 (d, J=1.61 Hz, 1H), 7.45 (d, J=8.59 Hz, 1H), 7.81 (dd, J=8.19, 1.48 Hz, 1H), 7.85 (s, 1H), 8.08 (d, J=8.06 Hz, 1H), 13.02 (s, 1H). ES-MS m/z 416 (M+H).