Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:29]3[CH:30]=[C:31](F)[CH:32]=[CH:33][C:28]3=[N:27][N:26]=2)[CH2:21][CH2:20]1)[CH:16]=[CH2:17].CC(O)=O>CN(C=O)C>[CH2:15]([O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:29]3[CH:30]=[C:31]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:32]=[CH:33][C:28]3=[N:27][N:26]=2)[CH2:23][CH2:24]1)[CH:16]=[CH2:17]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: C=CCOC1CCN(c2nnc3ccc(F)cn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=CCOC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A suspension of Intermediate A (108 mg, 0.661 mmol) and NaH (60% dispersion in oil, 72.1 mg, 180 mmol) in dry DMF (5 mL) at RT under Ar was stirred for 1 h (CARE: gas evolution). A solution of Intermediate 57a (166 mg, 0.601 mmol) in dry DMF (3 mL) was added and the dark brown solution stirred at 60° C. for 90 min. The solution was concentrated in vacuo, and the residue redissolved in MeOH (5 mL) and AcOH (0.171 mL, 3.00 mmol). The solution was applied to an SCX-2 cartridge (10 g) and was washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown solid. FCC, using 2-8% [2M NH3 in MeOH] in DCM, gave the title compound as a dark brown oil (204 mg, 81%). LCMS (Method 3): Rt 2.34 min, m/z 420 [MH+].
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]1([CH3:12])[O:10][CH2:9][CH:8]([OH:11])[CH2:7][O:6]1.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>C(N(CC)CC)C>[C:13]([O:11][CH:8]1[CH2:9][O:10][C:5]([CH3:12])([CH3:4])[O:6][CH2:7]1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: CC1(C)OCC(O)CO1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
To a CH2Cl2 (200 mL) solution of 2,2-dimethyl-1,3-dioxan-5-ol (17.0 g, 0.13 mol) at 0° C., triethylamine (20 mL) was added slowly. The reaction flask was flushed with nitrogen for 5 minutes. Methacryloyl chloride (13.5 g, 0.13 mol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, then filtered, washed with a water solution of NaHCO3 (1M, 2×200 mL) and distilled water (2×200 mL). The filtrate was dried over MgSO4. 1,4-hydroquinone (10 mg) was added as an inhibitor and solvent was removed. The oil was dissolved in ethyl acetate (50 mL) and passed through a silica gel plug. Solvent was removed and the product was purified by distillation, yielding a colorless oil product (18.5 g, 71%). 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 3H), 1.41 (s, 3H), 1.92 (s, 3H), 3.77 (d, 1H), 3.82 (d, 1H), 4.05 (d, 1H), 4.10 (d, 1H), 4.71 (m, 1H), 5.56 (s, 1H), 6.12 (s, 1H). 13C NMR (75.5 MHz, CDCl3) δ 19.2, 20.6, 23.0, 61.6, 63.2, 99.3, 123.2, 124.5, 138.1.
Reaction SMILES: Cl.Br[C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([CH3:11])[C:8]([Cl:12])=[N:7][N:6]2[CH:13]=1.[CH3:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:12][C:8]1[C:9]([CH3:11])=[C:10]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH3:14])=[CH:22][CH:21]=2)[C:5]2[N:6]([CH:13]=[CH:3][N:4]=2)[N:7]=1
Reactant: Cc1cc2nc(Br)cn2nc1Cl
Reactant: CCOc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(Nc2c(C)c(Cl)nn3ccnc23)cc1

Procedure:
(1d variation 2) To a mixture of bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine HCl salt (102 mg, 0.36 mmol) from 1c, in THF (1.5 ml) was added p-Phenetidine (49 mg, 0.36 mmol) and a 1.0 M solution of KOt-Bu in THF (3.0 eq, 1.08 ml, 1.08 mmol). The mixture was allowed to heat at 50 C for 1 hour. The solution was then concentrated in vacuo to dryness to provide 6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-amine as a solid. m/e 303 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[F:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[N:25]([CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](=[O:40])[C:23]2=[O:41].ClCCl>O1CCCC1>[C:34]1([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]2[C:26]3[C:22](=[CH:21][CH:20]=[CH:19][C:18]=3[F:17])[C:23]([OH:41])([C:8]3[C:9]([OH:11])=[CH:10][C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]=4[CH:7]=3)[C:24]2=[O:40])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(F)cccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C1(O)c1cc2c(cc1O)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a cooled (0° C.) suspension of 2,3-dihydro-1,4-benzodioxin-6-ol (0.47 g, 3.0 mmol) in anhydrous tetrahydrofuran (12 mL) was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 1.7 mL, 3.3 mmol). The reaction mixture was stirred at 0° C. for 1 h, and 7-fluoro-1-(diphenylmethyl)-1H-indole-2,3-dione (1.0 g, 3.0 mmol) and anhydrous dichloromethane (10 mL) were added. The reaction mixture was allowed to stir for 19 h at ambient temperature. The reaction mixture was concentrated in vacuo and was diluted with saturated aqueous ammonium chloride (30 mL) and ethyl acetate (30 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a 8% to 66% gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (1.22 g, 84%) as an off-white solid: MS (ES+) m/z 475.0 (M−17).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[C:38](=[N:40]O)[NH2:39]>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[C:38]1[N:40]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:29][N:39]=1
Reactant: NC(=NO)c1cc(F)ccc1F
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4cc(F)ccc4F)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 46.2 mg (0.269 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 72.5 mg (54% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])C(O)=O.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:11]([C:10]1[CH:9]=[CH:8][CH:4]=[CH:3][C:2]=1[OH:1])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 3-hydroxy-4-nitrobenzoic acid (1b) (1 g, 5.46 mmol), HOBt (1 g, 7.4 mmol), DIC (1,3-diisopropylcarbodiimide, 1 mL, 6.4 mmol), and an amino PEGA resin (1 g, 0.4 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: [N:1](=[C:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1)[OH:2].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C(Cl)Cl>[N:1]1[O:2][C:10](=[O:11])[N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:3]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: ON=C1CCCCCN1
Solvent: ClCCl
Product: O=c1onc2n1CCCCC2
Temperature: 25 °C
Reaction time: 144 h
Yield: 89.2 %

Procedure:
To a solution of 2 g (16 mmol) of 2-hydroximinohomopiperidine (Maybridge) in 20 mL of methylene chloride (CH2Cl2) was added 2.5 g (16 mmol) of 1,1′-carbonyldiimidazole (CDI). This was stirred at 25° C. for six days. This solution was diluted with CH2Cl2, washed with water, dried (MgSO4), filtered and concentrated to afford 2.2 g (89% yield) of the title compound as a white semi-solid. Mass Spectra for C7H10N2O2: M+H155. 1H NMR,(CDCl3) d 1.5-1.9 (m, 6H), 2.6 (dd, 2H), 3.6 (dd, 2H). 13C NMR (CDCl3) d 25.3, 26.0, 28.2, 30.2, 43.7, 159.1, 161.6.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([O:25][CH3:26])=[C:13]3[C:17]([C:18](=[O:24])[C:19]([O:21]CC)=[O:20])=[CH:16][NH:15][C:14]=23)[N:5]=1)[CH3:3].C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[OH:1][CH:2]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([O:25][CH3:26])=[C:13]3[C:17]([C:18](=[O:24])[C:19]([OH:21])=[O:20])=[CH:16][NH:15][C:14]=23)[N:5]=1)[CH3:3]
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(-n3cnc(C(C)O)n3)ncc(OC)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnc(-n2cnc(C(C)O)n2)c2[nH]cc(C(=O)C(=O)O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Ethyl 2-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (100 mg, 0.278 mmol) and K2CO3 (77 mg, 0.557 mmol) were dissolved in MeOH (2 mL) and water (2 mL). The mixture was stirred at room temperature overnight, and neutralized with 1N HCl to pH 3. All solvents were removed and the residue was purified by prep. HPLC to give 2-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (46 mg, 0.139 mmol, 49.9% yield). LCMS: m/z 332.1 (M+H)+, 1.17 min (method 8).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>CN(C)C=O>[CH2:24]([O:23][C:21]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a suspension of 1-(4-hydroxyphenyl)piperazine (50 g) and potassium carbonate (46.5 g) in N,N-dimethylformamide (100 ml) was added dropwise benzyl chloroformate (47.86 g) at 0 to 10° C., and stirred for 4 hours at ambient temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (30:1) to give 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid benzyl ester (60.8 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([SH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[C:18]1([S:24]([CH2:27][CH2:28][CH:29]2[CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:31][C:30]2=[O:43])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)C>[C:18]1([S:24]([CH2:27][CH2:28][CH:29]([CH:32]([S:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=2)[CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:30]([OH:43])=[O:31])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1OC(CCCCc2ccccc2)C1CCS(=O)(=O)c1ccccc1
Reactant: COc1ccc(S)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(SC(CCCCc2ccccc2)C(CCS(=O)(=O)c2ccccc2)C(=O)O)cc1OC
Yield: 78.4 %

Procedure:
To a vigorously stirring suspension of cesium carbonate (0.88 g, 2.69 mmol) in anhydrous DMF (10 mL) under a nitrogen atmosphere is added 3,4-dimethoxythiophenol (0.45 g, 2.69 mmol) in a dropwise fashion. The white heterogeneous mixture is stirred for 15 minutes then a solution containing (-)-3-(2-benzenesulfonylethyl)-4-(4-phenylbutyl)-oxetan-2-one (0.50 g, 1.34 mmol) in anhydrous DMF (4 mL) is added. The pale yellow heterogeneous mixture is stirred at room temperature for 2.5 hours then partitioned between water (50 mL) and diethyl ether (50 mL). Aqueous HCl (1 N, 5 mL) is added and the layers are separated. The aqueous phase is extracted with diethyl ether (2×20 mL) and the combined organic extracts are washed with water (10×10 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford a pale yellow oil. The crude product is chromatographed on silica gel (CH2Cl2 →CH2Cl2 :MeOH, 19:1) to afford a colorless oil which is dissolved in diethyl ether (100 mL) and washed with water (10×30 mL) to remove residual DMF. The organic phase is washed with brine (30 mL), dried over anhydrous MgSO4, filtered and concentrated to afford (-)-2-(2-benzenesulfonylethyl)-3-(3,4-dimethoxyphenyl-sulfanyl)-7-phenylheptanoic acid (0.57 g, 78%) as a white foam. TLC analysis [hexane/EtOAc, 2:1, Rf (lactone)=0.65, Rf (acid)=0.05]. [α]23D -35.3° (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.31-1.70 (m, 6H), 2.00 (m, 1H), 2.30 (m, 1H), 2.56 (m, 3H), 2.95 (m, 1H), 3.25 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.77 (d, J=8.2 Hz, 1H), 6.95 (m, 2H), 7.15 (m, 3H), 7.25 (m, 2H), 7.55 (m, 2H), 7.65 (m, 1H), 7.90 (m, 2H) ppm. Mass spectrum (FAB) m/z 542 (M)+.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>C(O)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][CH:10]2[CH2:12][CH2:11]2)[C:7]=1[NH2:8]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NC1CC1
Solvent: CCO
Product: Nc1c(Cl)ncnc1NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A stirred solution of 4,6-dichloropyrimidin-5-amine (10 g, 60.9 mmol) and cycloproplyamine (10.44 g, 182.93 mmol, 12.7 mL) in absolute ethanol (100 mL) wee heated at 125° C. in a sealed tube for 4 days. The reaction mixture was then concentrated under reduced pressure to give a yellow solid which was triturated with cold water (200 mL). The resulting slurry was stirred for one hour at room temperature and then filtered. The isolated solid was washed with water (2×25 mL) and dried under reduced pressure to give 11.32 g of the title compound as a pale yellow solid, which was used without any further purification.
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][CH:5]([CH2:14][NH:15][CH:16]=O)[CH2:4]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(Cl)Cl>[CH3:16][NH:15][CH2:14][CH:5]1[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:3]([CH3:1])[CH2:4]1
Reactant: O=CNCC1CCc2ccccc2N(C=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCC1CCc2ccccc2N(C)C1
Temperature: 10 °C

Procedure:
3.2 g of N-[(1-formyl-2,3,4,5-tetrahydro-[1H]-1-benzazepine-3-yl)-methyl] -formamide were added over 5 minutes to a temperature less than 20° C to a mixture of 3.2 g of lithium aluminum hydride in 60 ml of anhydrous tetrahydrofuran and the mixture was refluxed for an hour and then cooled to 10° C. 20 ml of tetrahydrofuran containing 40% water were added thereto dropwise and the mixture was filtered. The filtrate was washed with methylene chloride and was evaporated to dryness under reduced pressure to obtain 2.5 g of raw product. The latter was taken up in methylene chloride and the solution was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 2.5 g of [N, 1-dimethyl-2,3,4,5-tetrahydro-[1H]-1-benzazepine-3-methanamine].
Reaction SMILES: [C:1]([NH:20][CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29](O)=[O:30])=[O:23])([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.Br.Br.[S:34]1[C:38]2[CH2:39][CH:40]([NH2:43])[CH2:41][CH2:42][C:37]=2[N:36]=[C:35]1[NH2:44]>>[NH2:44][C:35]1[S:34][C:38]2[CH2:39][CH:40]([NH:43][C:29]([C@@H:25]3[CH2:26][CH2:27][CH2:28][N:24]3[C:22](=[O:23])[CH2:21][NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:30])[CH2:41][CH2:42][C:37]=2[N:36]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Br
Product: Nc1nc2c(s1)CC(NC(=O)[C@@H]1CCCN1C(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Yield: 36 %

Procedure:
The title compound was prepared from (2S)-1-[2-(Tritylamino)acetyl]-2-pyrrolidinecarboxylic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide according to the procedure described in EXAMPLE 25, and was obtained as a faint yellow crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[C:4]([C:5]([O:7]CC)=[O:6])=[C:3]1[CH3:20].[OH-].[Na+]>>[CH3:1][N:2]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:19])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[CH3:20]
Reactant: CCOC(=O)c1c(C)n(C)cc(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)O)c(=O)c(-c2ccccc2)cn1C

Procedure:
5.8 g. of ethyl 1,2-dimethyl-5-phenyl-4-oxonicotinate was suspended in 60 ml. of 5% aqueous NaOH solution and heated on a steambath for 21/2 hours. The mixture was cooled and acidified. The resulting solid was recrystallized from acetonitrile to yield 1,2-dimethyl-5-phenyl-4-oxonicotinic acid as tan needles. m.p.=227°-228° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Product: Cc1ccc(C(=O)Cl)cc1S(N)(=O)=O

Procedure:
10 g of 4-methyl-3-sulfamoylbenzoic acid were boiled under reflux for 8 hours in 50 ml of thionyl chloride and the reaction mixture was allowed to stand over night at 0° C. The crystals were collected on a sinter glass frit and washed with petroleum ether and diisopropyl ether. Melting point: 180° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.N1C=CC=CC=1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([NH:1][S:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:43])=[O:42])[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(N)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(NS(=O)(=O)c3ccccc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1

Procedure:
6-amino-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (30 mg, 0.079 mmol) was suspended in DCM (3 mL) followed by pyridine (0.032 mL, 0.395 mmol). The contents were vigorously stirred and then benzenesulfonyl chloride (0.011 mL, 0.087 mmol) was added and the contents stirred at RT for 1 h. The volatiles were removed in vacuo and dried on hi-vac for 1 h. The crude product was purified by reverse phase HPLC (Gradient B: 15-70%. A: Water+0.1% TFA. B: CH3CN+0.1% TFA). The product was neutralized with water and sat. NaHCO3, and extracted with 10% THF/EtOAC (hot) in duplicate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The solid was concentrated from DCM and dried in vacuum oven for 4 h at 45° C. The title compound was collected as 30 mg (72%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (td, J=5.49, 3.41 Hz, 2H), 1.75-1.94 (m, 4H), 1.99-2.10 (m, 2H), 2.12 (s, 3H), 2.20 (s, 3H), 4.30 (d, J=5.05 Hz, 2H), 4.89-5.04 (m, 1H), 5.89 (s, 1H), 7.22 (d, J=1.52 Hz, 1H), 7.36 (s, 1H), 7.48-7.63 (m, 3H), 7.77-7.84 (m, 2H), 8.11 (s, 1H), 8.36 (t, J=5.05 Hz, 1H), 10.56 (s, 1H), 11.55 (s, 1H); LC-MS (ES) m/z=519.2 [M+H]
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:16]([C:18]1[C:19]([CH3:27])=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22])#[N:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]#[N:17])[C:19]=2[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1c(C#N)cccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C#N)c2C)Cc2ccccc2C1
Yield: 89.2 %

Procedure:
2-Amino-indane-2-carboxylic acid ethyl ester (250 mg, 1.2 mmol), 3-cyano-2-methyl-benzoic acid (196 mg, 1.2 mmol) and HATU (555 mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen. Anhydrous DMF (2 mL) is added and stirring is initiated. After a few min, DIPEA (0.302 mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. Water (10 mL) is added, extracted with EtOAc (3×5 mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20-50% EtOAc in heptane as a gradient to afford 2-(3-cyano-2-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (373 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:6][CH:7]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:17]2[O:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: Oc1ccccc1-c1ccc(Cl)nn1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Clc1ccc(-c2ccccc2OCC2CO2)nn1

Procedure:
A mixture of 3-chloro-6-(2-hydroxyphenyl)pyridazine (2.69 g.), epibromohydrin (4.5 ml.), anhydrous potassium carbonate (3.6 g.) and dry butane-2-one (100 ml.) was stirred and heated under reflux for 16 hours. The mixture was filtered and the filtrate was evaporated to dryness and the residue was twice recrystallized from ethanol to give 3-chloro-6-(2-epoxypropoxyphenyl)pyridazine, m.p. 118°-119°.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][N:29]([C:37](=[O:36])[CH2:38][OH:39])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CN(C(=O)CO)C[C@H]1O

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f10) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.