Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:36]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CCO
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carboxamide (Preparation 5) (420 mg, 0.76 mmol) in ethanol (20 ml) was treated with hydrochloric acid (2 M, 0.9 ml). The mixture was heated at reflux for 30 minutes after which time a white precipitate had formed. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and 10% weight by volume aqueous ammonia. The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound as a white solid (319 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:9][CH:10]=1)=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][CH2:12][CH2:13][NH:14][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:9][CH:10]=1)=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CCCN)o1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCNS(C)(=O)=O)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of 5-(3-amino-propyl)-furan-2-carboxylic Acid methyl ester hydrochloride salt (see Preparation DD2) (150 mg, 0.683 mmol), and triethylamine (0.313 mL, 2.25 mmol) in CH2Cl2 (15 mL) at 0° C. was added methanesulfonyl chloride (86 mg, 0.75 mmol). The reaction was stirred at room temperature for 18 h. The organic solution was washed consecutively with dilute HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title sulfonamide (156 mg). MS 262 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH2:31][CH2:32]N.C(N(CC)CC)C>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]4[N:30]([CH3:29])[CH2:31][CH2:32][N:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:26])([F:27])[F:28])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC#N)CC3)cc1
Reactant: CNCCN
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC2=NCCN2C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-pentanenitrile (0.200 g, 0.510 mmol) was dissolved in 1:1 MeOH/CHCl3 (25 mL). Hydrogen chloride gas was bubbled through the solution for 15 min. The reaction was tightly capped and sealed, stirred overnight at rt, and then concentrated to dryness. The crude intermediate was dissolved in methanol (15 mL). N-Methylethylenediamine (0.04 mL, 0.510 mmol) and triethylamine (0.36 mL, 2.55 mmol) were added. The reaction was tightly capped and sealed and stirred overnight at rt. The reaction was concentrated and purified by reverse phase HPLC and freeze-dried to yield the title compound (0.184 g, 80%): 1H NMR (CHCl3) δ 7.43 (d, j=9.1 Hz, 2H), 6.95 (d, j=9.1 Hz, 2H), 3.95–3.83 (m, 2H), 3.85 (s, 3H), 3.71 (t, j=6.8 Hz, 2H), 3.58–3.50(m, 4H), 3.03 (t, j=7.9 Hz, 2H), 3.00(s, 2H), 2.68 (s, 4H), 1.73 (bs, 4H) ppm; Mass Spec 450.0(M+H)+.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH:17]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]([Br:24])[CH:18]=1>>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[O:23][C:22]1[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][CH:17]=1)[CH3:12]
Reactant: CCOC(=O)Cn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(Br)cc1
Product: CCOC(=O)Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a mixture of ethyl 2-(2-chloro-1H-benzo[d]imidazol-1-yl)acetate (11.0 g) and p-bromophenol (23.9 g) was added TEA (19.2 mL) at room temperature. After stirring overnight at 120° C., the reaction mixture was quenched with water and extracted with AcOEt. The organic layer was separated, washed with 1 M NaOH aqueous solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (11.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].O.C(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cccc(F)c1
Agent: O=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(F)c1
Yield: 48.1 %

Procedure:
To a cooled (ice bath) solution of 11.2 g (0.1 mole) of 3-fluorophenol (98%, Aldrich) in 75 ml of toluene was added 9.1 ml (14.8 g, 0.105 mol) of chlorosulfonyl isocyanate, and the solution heated at reflux overnight. The solution was cooled and cautiously treated dropwise with water until carbon dioxide evolution ceased. An oil separated and ethyl acetate was added to dissolve this oil. The layers were separated and the organic layer was washed with water, dried (sodium sulfate) and concentrated to give an oil which gradually crystallized. The solid was purified by column chromatography on 400 g of silica gel eluted with methylene chloride. The appropriate fractions were combined and concentrated to yield 9.2 g (48%) of the title compound which was recrystallized from benzene to give a white solid, mp 53°-55° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([Cl:17])=[CH:12][CH:13]=2)[N:8]([CH:18]2[CH2:20][CH2:19]2)[CH:7]=1)=[O:5])C>Cl>[Cl:17][C:11]1[N:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]2[CH:18]2[CH2:20][CH2:19]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)ccc2c1=O
Agent: Cl
Product: O=C(O)c1cn(C2CC2)c2nc(Cl)ccc2c1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared according to EP 607825; 500 mg) in 6N HCl (6 ml) was stirred at 100° C. for 30 min. The reaction mixture was allowed to reach rt and the resulting crystals were collected by filtration and sequentially washed with water and MeOH, affording a beige solid.
Reaction SMILES: [C:1]([C:8]([O:10][CH2:11][CH3:12])=[O:9])#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:13][C:14]1[CH:20]=[CH:19][C:18](=[O:21])[C:17]([OH:22])=[CH:16][CH:15]=1>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:13][C:14]1[CH:20]=[CH:19][C:18](=[O:21])[C:17]([OH:22])=[CH:16][CH:15]=1)=[CH:1][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:7]
Reactant: Nc1ccc(O)c(=O)cc1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C=C(Nc1ccc(O)c(=O)cc1)C(=O)OCC

Procedure:
A solution of diethyl acetylenedicarboxylate (183.5 g) and 5-amino-2-hydroxy-2,4,6-cycloheptatriene-1-one [147.5 g, described by T. Nozoe et al., Science Repts. Tokoku Univ., First ser., 35, 274(1952)] in ethanol (2,700 ml) is stirred at room temperature for 16 hours. The mixture is filtered and the precipitate is crystallized from ethanol to obtain crystals of the title compound, mp 108.5° C.
Reaction SMILES: [C:1]([OH:4])#[C:2][CH3:3].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.Cl>>[C:1]([O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1)#[C:2][CH3:3]
Reactant: C1=COCCC1
Reactant: CC#CO
Agent: Cl
Product: CC#COC1CCCCO1

Procedure:
Prop-1-ynol was added to dihydropyran in the presence of hydrochloric acid to give prop-1-ynyltetrahydropyranyl ether. The ether was alkylated with 5-methylhexyl bromide. The resultant product was hydrolyzed with sulfuric acid to the desired alcohol, 8-methylnon-2yn-1-ol.
Reaction SMILES: [N+:1]([CH:4]([N+:9]([O-:11])=[O:10])[CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([O:8][CH2:7][CH2:6][CH2:5][CH:4]([N+:9]([O-:11])=[O:10])[N+:1]([O-:3])=[O:2])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])C(CCCO)[N+](=O)[O-]
Solvent: ClCCl
Product: CC(=O)OCCCC([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
This ester was synthesized by treating a solution of 4,4-dinitro-1-butanol (39.2 g, 0.24 mols) in CH2Cl2 (100 ml) with acetyl chloride (22 ml, 24 g, 0.31 mol). After 90 minutes at room temperature, the reaction was quenched with ice water. Separation, drying (MgSO4), and concentration of the organic phase gave the product (42.7 g, 87%) as a light yellow oil; nD =1.4574 (24C). The infrared spectrum of the product had peaks at 2960, 1745, 1575, 1245, and 1060 cm-1. Elemental analyses-Calculated for C6H10N2O6 : C, 34.95; H, 4.85; N, 13.59; Found: C, 35.17; H, 4.83; N, 12.95.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[N:4]=[C:3]1[C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[CH:23][CH:22]=1.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[C:26]1([N:25]2[C:21]([C:3]3[C:2](=[O:1])[CH:7]=[CH:6][N:5]([CH:8]4[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]4)[N:4]=3)=[CH:22][CH:23]=[N:24]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1ccn(C2CCCNC2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 3-[4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]piperidine-1-carboxylate (15.9 g) in dichloromethane (76 mL) was added 4M hydrogen chloride in 1,4-dioxane solution (9.4 mL) at 0° C., and the mixture was stirred at room temperature for 24 hr. The solvent was evaporated under reduced pressure to give the title compound (12.1 g).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[NH:21][N:22]=[N:23][CH:24]=2)=[O:19])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]O>Cl.O1CCOCC1>[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:12][C:11](=[O:13])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH:17][C:18]([C:20]1[NH:21][N:22]=[N:23][CH:24]=1)=[O:19])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Reactant: COCCOCCO
Agent: Cl
Solvent: C1COCCO1
Product: COCCOCCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 65 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (100 mg, 245 μmol, 1.0 eq) was dissolved in 4 M of HCl in dioxane (0.6 mL) and 2-(2-methoxyethoxy)-ethanol (3 mL). The resulting mixture was stirred overnight at 65° C. The solvent was evaporated and AcOH was added. The product was then purified by preparative HPLC to yield the title compound (70 mg, 95% purity). MS m/z [M+H]+ calc'd for C22H34N4O6, 511.25. found 511.4
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=O)[N:6]2[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:58][N:59]([CH3:68])[C:60]1[CH:67]=[CH:66][C:63]([CH2:64][NH2:65])=[CH:62][CH:61]=1>CN(C=O)C>[CH3:58][N:59]([CH3:68])[C:60]1[CH:67]=[CH:66][C:63]([CH2:64][NH:65][C:12]([C:5]2[N:6]([CH3:11])[C:7]3[C:3]([CH:4]=2)=[C:2]([OH:1])[CH:10]=[CH:9][CH:8]=3)=[O:14])=[CH:62][CH:61]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: Cn1c(C(=O)O)cc2c(O)cccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)c1ccc(CNC(=O)c2cc3c(O)cccc3n2C)cc1
Reaction time: 0.08 h
Yield: 69 %

Procedure:
To a solution of 4-hydroxy-1-methyl-1H-indole-2-carboxylic acid (Example 10, 0.12 g) in DMF (10 mL) was added TBTU (0.20 g), HOBt (0.10 g) and DIEA (0.35 mL). After 5 min. 4-(dimethylamino)benzylamine dihydrochloride (0.14 g) was added and stirring was continued overnight under nitrogen at room temperature. The residue remaining after DMF evaporation was purified by reversed phased chromatography on C18 silica with a trifluoroacetic acid (0.025%) acidified acetonitrile water gradient to give 0.14 g of the title compound. MS ES (M++H)=324.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[C:13](=[O:14])[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=O.[BH3-]C#N.[Na+]>C1COCC1.CCO.CC(O)=O>[CH2:34]([O:33][C:29](=[O:32])[CH2:30][NH:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[C:13](=[O:14])[NH:12][C:11]3=[CH:15][CH:16]=[CH:17][CH2:18][C:10]3=[CH:9][CH2:8]2)=[CH:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:35]
Reactant: Nc1ccc(OC2CCc3ccccc3NC2=O)cc1OCc1ccccc1
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CNc1ccc(OC2CC=C3CC=CC=C3NC2=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-(4-amino-3-benzyloxyphenoxy)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (7.4 mmol) and ethyl glyoxylate (1.44 mL, 7.4 mmol) in THF (5 mL) is stirred at RT for 5 h. The mixture is diluted with 38 mL of EtOH/HOAc (9:1) then NaCNBH3 (0.91 g, 14 mmol) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure and the residue triturated with water. The solid is purified by column chromatography using a gradient of 33-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([OH:17])[C:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:15]=2[CH:16]=1.O[C@H:19]([C@H:21]1[CH2:25][N:24]([C@H](C2C=CC(OC)=CC=2)C)[C:23](=[O:36])[CH2:22]1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[C:9]([O:17][C@@H:19]([C@H:21]2[CH2:25][NH:24][C:23](=[O:36])[CH2:22]2)[CH3:20])[CH:8]=1
Reactant: COc1ccc([C@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Reactant: Oc1cc(-c2ccccn2)cc2ncccc12
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccccn2)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
20 mg of 7-(Pyridin-2-yl)quinolin-5-ol, 30 mg of ((R)-4-((S)-1-hydroxyethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one and 50 mg of triphenylphosphin was dissolved in 2 mL of DCM. 45 mg of DBAD was added and the mixture stirred for 14 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and dissolved in 0.5 mL of TFA and heated 30 min at 90° C. in the microwave. The mixture was purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 21 mg of Example 6 as solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([NH2:16])=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]2[CH2:15][CH2:14][CH:12]3[CH2:13][N:3]([CH2:1][CH3:2])[CH2:4]2)=[N:19][CH:20]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC2CCC(C1)c1cc(N)ccc12
Product: CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)NC)n3)ccc12

Procedure:
2-[5-Chloro-2-(10-ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide was prepared from 10-ethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide in an analogous manner to Example 271. Product isolated as a clear thin film (13 mg, 18%). LCMS (m/e) 513 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.13 (s, 1H), 8.48 (d, 1H, J=8.4 Hz), 8.01 (s, 1H), 7.95 (d, 1H, J=7.9 Hz), 7.55 (t, 1H, J=7.7 Hz), 7.27-7.20 (m, 2H), 7.06 (s, 1H), 6.99 (d, 1H, J=8.5 Hz), 5.11 (bs, 1H), 3.00-2.80 (m, 4H), 2.63 (s, 3H), 2.44 (q, 2H, J=6.7 Hz), 2.30-2.10 (m, 4H), 1.62-1.58 (m, 2H), 1.01 (t, 3H, J=7.0 Hz).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH3:15]>CCO>[NH2:15][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: N
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Solvent: CCO
Product: NCC(O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 96 %

Procedure:
To a solution of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (17 g, 0.09 mol) in EtOH (300 mL) at −78° C. was slowly bubbled NH3 (g). The reaction mixture was then sealed and heated at 80° C. for 3 h. The reaction mixture was concentrated and the crude product was used in next step without further purification (18 g, Yield 96%). LCMS (m/z): 207.1 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)[CH:16]=[N:15][CH:14]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc(F)c(Cl)c3)n2)c1
Yield: 4.7 %

Procedure:
Using Method K. 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 3-chloro-4-fluoroaniline (42 mg, 0.29 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 80° C. for 12 hours. The same workup as for Method K and a combination of column chromatography and preparative TLC furnished 4 mg of title compound. Yield: 4.7%. 1H NMR (250 MHz, DMSO-d6) δ 2.09 (s, 3 H), 7.38 (d, 1 H, J=9.5 Hz), 7.46 (d, 1 H. J=7.9 Hz), 7.61 (d, 1 H, J=7.9 Hz), 7.72 (d, 1 H, 7.5 Hz), 7.86-7.91 (m, 1 H), 8.00-8-04 (m, 1H), 8.18 (s, 1 H), 8.40 (bs, 1 H), 8.48 (s, 1 H), 9.80 (s, 1 H), 10.08 (s, 1 H); m/z 357.2 [(M+H)+, calcd for C18H14ClFN4O 356.1].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:29]=[N:28][N:27]([CH:30]([CH3:32])[CH3:31])[C:16]=2[N:17]=[C:18]([N:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[CH:19]=1)=[O:13].[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:29]=[N:28][N:27]([CH:30]([CH3:32])[CH3:31])[C:16]=2[N:17]=[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(N3CCC(=O)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCC(O)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.9 %

Procedure:
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(4-oxopiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.1 g, 0.229 mmol) was taken in MeOH (3 mL) and NaBH4 (0.020 g, 0.458 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 4 h. On completion of reaction, MeOH was concentrated. And residue was purified by prep HPLC to provide the desired compound (0.034 g, 34%). LCMS: 439.20 (M+1)+; HPLC: 98.22% (@ 254 nm), (Rt; 5.393); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 8.63 (bs, 1H), 7.97 (s, 1H), 7.11 (s, 1H), 5.88 (s, 1H), 4.98-4.95 (m, 1H), 4.34 (d, 2H, J=4.4 Hz), 4.15 (m, 2H), 3.74-3.72 (m, 1H), 3.23 (m, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.82 (m, 2H), 1.43 (d, 6H, J=6.4 Hz), 1.38 (m, 2H).
Reaction SMILES: [In:1].[C:2]([O-:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([O-:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[NH4+].[NH4+].[NH4+]>Cl.O>[C:2]([O-:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([O-:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[In+3:1]
Reactant: [In]
Agent: Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: [In+3]

Procedure:
Indium foil (226.3 mg) is dissolved in HCl and diluted with H2O to give 1.97×103 mol per 100 ml in 0.6 N HCl. Indium citrate solution is prepared by mixing 5 ul of 1.97×10-2M InCl3 (9.85×10-8 mol) with 94 ul of 0.1M ammonium citrate, pH 5.58 to give 9.85×10-4M indium citrate after addition of 1 ul of 111In (13 uCi) in 0.1M ammonium citrate.
Reaction SMILES: Cl[Si](C)(C)C.C[O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]#[C:15][CH3:16])=[CH:10][N:9]=1.[Na+].[I-]>C(#N)C>[C:14]([C:11]1[CH:10]=[N:9][C:8](=[O:7])[NH:13][CH:12]=1)#[C:15][CH3:16]
Reactant: CC#Cc1cnc(OC)nc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC#Cc1cnc(=O)[nH]c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Chlorotrimethylsilane (4.11 ml; 32.5 mmol) was introduced by syringe, into a solution of 1.5 g (10.2 mmol) of the 2-methoxy-5-(1-propynyl)pyrimidine and 4.56 g (30.44 mmol) of NaI in 35 ml of anhydrous acetonitrile maintained under an atmosphere of dry nitrogen and removed from light. The mixture was stirred at 50° C. for 21/2 hours with periodic monitoring by tlc. The mixture was cooled in an ice-bath and 3.5 g (8.14 mmol) of the halogenose, 1-(3,5-di-O-(p-chlorobenzoyl)-2-deoxy-α-D-ribofuranosyl)-chloride were then added. To this mixture was added 3 ml of 1N trimethylsilyl triflate in 1,2-dichloroethane; the mixture was stirred at 0° C. for 1 hour and then at room temperature for 21/2 hours. The reaction mixture was then diluted with dichloromethane (150 ml) and saturated aqueous bicarbonate (65 ml). The organic extract was subsequently washed with water (60 ml), dried over magnesium sulfate and concentrated to a residue which was subjected to flash chromatography on 80 g of silica gel. The fractions containing the slower moving alpha anomer were pooled and concentrated to a minimum volume with attendant precipitation. The mixture was cooled and filtered; the white product washed with diethyl ether and dried at 50° C. to provide 1.1 g (25.7%) of 1-(3,5-di-O-)p-chlorobenzoyl)-2-deoxy-α-D-ribofuranosyl)-5-(1-propynyl)-2-pyrimidinone; mp 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][N:10]=[C:11]2[CH3:12]
Reactant: CC(=O)NCCc1ccccc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2c(Cl)cccc21

Procedure:
In close analogy to the procedure described above, N-[2-(2-chloro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.