Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2O)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH:22]([O:21][C:19]([C:17]1[N:16]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[CH:15]=[N:14][CH:18]=1)=[O:20])([CH3:24])[CH3:23]
Reactant: N#Cc1ccc2c(c1)C(O)CCC2
Reactant: CC(C)OC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cncn1C1CCCc2ccc(C#N)cc21

Procedure:
To a suspension of 7-cyano-1,2,3,4-tetrahydro-naphthalen-1-ol (0.298 g, 1.72 mmol) and isopropyl 4-imidazolecarboxylate (0.185 g, 1.204 mmol), which can be prepared as described in Example 1, in THF (10 mL) at 0° C. is added triphenylphosphine (0.451 g, 1.72 mmol), followed by diisopropyl azodicarboxylate (94%, 0.369 g, 1.72 mmol). After 1 hour the mixture is diluted with ethyl acetate and washed with water. The organic phase is dried over MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 3-(7-cyano-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 310.1 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(7-cyano-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.36 (d, J=6.1 Hz, 3 H), 1.39 (d, J=6.3 Hz, 3 H), 1.90-1.98 (m, 2 H), 2.29-2.33 (m, 2 H), 2.97 (dt, J=17.7, 6.3 Hz, 1 H), 3.12 (dd, J=17.7, 6.8 Hz, 1 H), 5.21 (sept, J=6.3 Hz, 1 H), 6.35 (t, J=6.3 Hz, 1 H), 7.25 (s, 1 H), 7.45 (d, J=8.1 Hz, 1 H), 7.59 (s, 1 H), 7.62 (dd, J=8.1, 1.5 Hz, 1 H), 7.78 (d, J=1.5 Hz, 1 H).
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([CH2:14][C:15]([NH:17][NH2:18])=[O:16])[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([S:27]([N:30]=[C:31]=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCOCC1.CO>[CH3:33][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[O:16][C:15]([CH2:14][C:12]3[S:13][C:9]4[CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:20]=[CH:19][C:10]=4[N:11]=3)=[N:17][N:18]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: NNC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Nc2nnc(Cc3nc4ccc(-c5ccccc5)cc4s3)o2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
To a suspension of 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (26 mg, 0.092 mmol) (described in WO 2011/074560) in dioxane (0.8 mL) was added p-toluenesulfonyl isocyanate (15 μL, 0.10 mmol), and the reaction mixture stirred for 15 min. 1-Propanephosphonic acid cyclic anhydride (50% in EtOAc) (0.164 mL, 0.275 mmol) was added and the reaction mixture stirred at 105° C. for 18 h. The reaction mixture was allowed to cool to rt, diluted with MeOH then purified by preparative HPLC (RT=8.79 min using Axia Luna 5 u C18 30×100 mm column with flow rate of 40 mL/min over 10 min period. Solvent A=10/90/0.1% ACN/H2O/TFA, Solvent B=90/10/0.1%, 10 to 100% B). The fraction containing product was evaporated to dryness and the residue chromatographed on silica gel eluting with 0 to 10% MeOH/DCM to give Compound 90a (5 mg, 12%) as a white solid. LCMS=1.01 min using analytical method (M), 462.9 (M+H). 1H NMR (400 MHz, CDCl3, 60° C.) δ 8.08-7.99 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.59 (d, J=7.0 Hz, 2H), 7.48-7.39 (m, 2H), 7.36 (t, J=7.0 Hz, 1H), 7.24 (d, J=4.3 Hz, 2H), 4.50-4.44 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]>[N+](C1C=CC=CC=1)([O-])=O>[F:10][C:11]1[CH:16]=[C:15]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:9])[CH3:1])[CH:14]=[CH:13][C:12]=1[O:17][CH3:18]
Reactant: COc1ccccc1F
Reactant: CC(C)CCCC(=O)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCCC(C)C)cc1F
Temperature: 0 °C

Procedure:
14 ml of nitrobenzene are cooled in an ice-bath and then mixed in succession with 3.8 g of AICl3 and 3.7 g of 5-methyl-hexanoyl chloride in 5 ml of nitrobenzene. The mixture is stirred and then treated with 2.7 ml of 2-fluoro-anisole. The solution is stirred overnight, then poured into ice-water and extracted with methylene chloride. The extracts are washed with water and 10% aqueous NaCl solution, and thereafter dried and concentrated and recrystallized using pentane. 5.31 g of 1-(3-fluoro-4-methoxy-phenyl)-5-methyl-hexan-1-one, MS: m/e 238 (M+), are obtained.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CN(C)C=O>[F:33][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCC(N2CCOCC2)CC1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a brown oil (56%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].[C:17](=O)([O:25]C1C=CC([N+]([O-])=O)=CC=1)[O:18][CH:19]([O:21][C:22](=[O:24])[CH3:23])[CH3:20].C(N(CC)CC)C>ClCCl>[C:22]([O:21][CH:19]([O:18][C:17]([NH:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:25])[CH3:20])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)OC(C)=O)C(=O)N1CCC[C@H]1C#N
Yield: 69.6 %

Procedure:
A solution of (2S)-1-(isoleucyl)pyrrolidine-2-carbonitrile hydrochloride (500 mg, 2.04 mmol; prepared according to Jenkins et al., WO95/15309), α-acetoxyethyl p-nitrophenyl carbonate (610 mg, 2.27 mmol; prepared according to Alexander et al., J. Med. Chem. 31, 318, 1988) and triethylamine (250 mg, 2.50 mmol) in dichloromethane (40 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60–80° C.; 3:7) yielding a colourless oil identified as the title compound (480 mg, 1.42 mmol, 70%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].[CH3:27]I.O>CN(C=O)C>[CH3:27][O:19][C:18]([C:15]1[C:16]2[O:17][C:6]3[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=[C:2]([CH3:1])[C:7]=3[C:8](=[O:9])[O:10][C:11]=2[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=1)=[O:20]
Reactant: CI
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Temperature: 25 °C

Procedure:
Psoromic acid (1 mmol) was dissolved in DMF (10 mL), KHCO3 (2.4 mmol) was added and stirred for several minutes at room temperature. Then, CH3I (1.2 mmol) was added. The reaction mixture was maintained at 40° C. and monitored by TLC. Upon completion, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate. The organic layer was subsequently washed with saturated NaHCO3 solution and saturated brine, and dried over anhydrous MgSO4, filtered and evaporated by a rotatory evaporator. The residue was purified by column chromatography to provide a white solid product.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.CO>C1COCC1>[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCOCC1
Yield: 84.7 %

Procedure:
Sodium hydroxide (7.05 mL, 12.5 M, 88 mmol) was added dropwise to a solution of methyl tetrahydro-2H-pyran-4-carboxylate (2.54 g, 17.6 mmol) in a mix of methanol (30 mL) and THF (30 mL) at 25° C. The reaction was stirred over the weekend. The THF/MeOH was then evaporated and the crude was washed with Et2O (2×). The aqueous layer was acidified and extracted with EtOAc (2×); the organics were dried over Na2SO4, filtered and the solvent was evaporated to give the title compound (D8) (1.94 g, 76%) as a white solid.
Reaction SMILES: C(OC([C:6]1[N:7]([CH2:17][CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[Br:16])=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:16][C:9]1[C:8]2[N:7]3[CH2:17][CH2:18][NH:19][C:20](=[O:22])[C:6]3=[CH:14][C:13]=2[CH:12]=[C:11]([F:15])[CH:10]=1
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2n1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
To a stirred solution of ethyl 7-bromo-1-(2-(tert-butoxycarbonylamino)ethyl)-5-fluoro-1H-indole-2-carboxylate (step A) (1.43 g, 3.33 mmol) in dichloromethane (15.2 ml) was added drop wise at 0° C. trifluoroacetic acid (4.79 g, 3.23 ml, 42.0 mmol). Afterwards the solution was allowed to stir for 15 min at 0° C., and for 30 min at room temperature. The reaction mixture was evaporated and the remaining material was solved in methanol (15.2 ml). Potassium carbonate (1.83 g, 13.3 mmol) was added and the mixture was allowed to stir at room temperature for 17 h. The mixture was evaporated, water (50 ml) was added and the mixture was extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product (0.86 g) was purified by trituration with dichloromethane (3 ml) and heptane (15 ml) to yield the title compound as an off-white solid (0.85 g, 90%), MS (ISN) m/z=283.2 [(M+H)+], mp 253.5° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N+:23]([O-:9])[CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccc[n+]([O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
m-Chloroperbenzoic acid (6.9 g, 40.0 mmol) was slowly added to a solution of 3-(4-nitrophenyl)pyridine (P1, 4 g, 20.0 mmol) in tetrahydrofuran (200 mL) and the reaction mixture was stirred at room temperature for 1 hour. The solution was poured into aqueous sodium thiosulfate and the resultant mixture was concentrated. Trituration with ethyl acetate afforded the title compound as a solid.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[CH3:29][C:30](C)=[O:31].C(Cl)(=O)C.N.O>O>[C:30]([O:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:31])[CH3:29]
Reactant: O=C1CCc2c(cccc2OCC(O)CN2CCN(c3ccccc3)CC2)N1
Reactant: CC(C)=O
Agent: N
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)OC(COc1cccc2c1CCC(=O)N2)CN1CCN(c2ccccc2)CC1

Procedure:
2 Grams of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril are mixed with 30 ml of acetone and further 12 ml of acetyl chloride are added followed by heating for 10 hours under refluxing conditions. After cooling the reaction mixture, the product precipitated is collectd by filtration and washed with acetone. The crude crystals thus obtained are dissolved in 80 ml of water and made basic with ammonia-water, then extracted with chloroform, dried and chloroform is removed by distillation. The residue is purified by silica gel chromatography to obtain 0.5 g of 5-[2-acetyloxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 159°-161° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[C:9](=[O:23])[NH:10][C:11]([NH:16]C(=O)C(C)(C)C)=[N:12][C:13]=3[CH:14]=[CH:15][C:6]=2[CH:5]=[CH:4][C:3]=1[Br:24].[OH-].[Na+].NC1NC(=O)C2C3C=C(Br)C=CC=3C=CC=2N=1>>[NH2:16][C:11]1[NH:10][C:9](=[O:23])[C:8]2[C:7]3[C:2]([NH2:1])=[C:3]([Br:24])[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(Br)c(N)c3c2c(=O)[nH]1
Agent: Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ccc3ccc(Br)c(N)c3c2c(=O)[nH]1

Procedure:
N-(10-Amino-9-bromo-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.58 g, 1.5 mmoles) was reacted with aqueous sodium hydroxide as described for the analogous 9-bromo compound (example 2). The product was precipitated from the reaction mixture with acetic acid, filtered and washed with water to give 3,10-diamino-9-bromobenzo[f]quinazolin-1(2H)-one as a yellow solid. (0.36 g, 80%) 1H NMR (DMSO-d6, 200 MHz) δ: 6.49 (br s, 2H, NH2); 6.69(br s, 2H, NH2); 7.09(d, J=8.4 Hz, 1H, Ar); 7.22(d, J=8.9 Hz, 1H, Ar); 7.56(d, J=8.4 Hz, 1H, Ar); 7.09(d, J=8.9 Hz, 1H, Ar); 11.47(br s, 1H, NH).
Reaction SMILES: [CH:1]([C:3]1[N:34]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[C:6]2=[N:7][CH:8]=[CH:9][C:10]([C:11]3[C:12]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:26])=[CH:20][CH:19]=4)=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=3)=[C:5]2[CH:4]=1)=O.[NH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:16]([N:14]1[CH:15]=[C:11]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[N:34]([S:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)(=[O:36])=[O:37])[C:3]([CH2:1][NH:44][CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[CH:4][C:5]=23)[C:12]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:20][CH:19]=2)=[N:13]1)[CH3:17]
Reactant: CCn1cc(-c2ccnc3c2cc(C=O)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: NCCN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCn1cc(-c2ccnc3c2cc(CNCCN2CCOCC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1

Procedure:
A solution of N-(4-{4-[2-formyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl}phenyl)-N′-phenylurea (0.1 mmol), 4-(2-aminoethyl)-morpholine (0.2 mmol), and sodium triacetoxyborohydride (0.2 mmol) in dichloromethane (1 mL) and acetic acid (0.25 mL) under nitrogen was stirred at room temperature for 30 minutes. The reaction was quenched with 1N sodium hydroxide solution (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, and concentrated in vacuo to give the title compound as the crude product. ESMS [M+H]+: 705.6
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:20])[C:10]3[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:23](NNC=O)=[O:24]>ClCCl>[CH3:16][N:15]1[C:10]2[C:9](=[O:20])[NH:8][C:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][CH:23]=[O:24])=[CH:3][CH:4]=3)=[N:12][C:11]=2[C:13]([CH2:17][CH2:18][CH3:19])=[N:14]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Reactant: O=CNNC=O
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC=O)cc3)nc12
Temperature: 200 °C
Reaction time: 0.92 h
Yield: 52.2 %

Procedure:
A mixture of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrimidin-7-one (297 mg, 0.0010 mol) and 1,2-diformylhydrazine (101 mg, 0.00115 mol) was heated to 200° C. The resulting melt was then stirred under a nitrogen atmosphere at this temperature for 55 minutes. On cooling, the solid was dissolved in dichloromethane:methanol, pre-absorbed onto silica and purified by flash column chromatography eluting with a solvent gradient of dichloromethane:methanol (99:1 to 96:4 by volume) then dichloromethane:methanol:0.880 aqueous ammonia (90:10:1 by volume). Crystallisation from ethyl acetate/methanol gave the title compound (170 mg), m.p.260-261° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][CH:12]1[CH2:21][CH2:20][CH2:19][C:18]2[N:17]=[C:16](C#N)[CH:15]=[CH:14][C:13]1=2.[C:24](=[O:27])(O)[O-:25].[Na+]>Br.O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][CH:12]1[CH2:21][CH2:20][CH2:19][C:18]2[N:17]=[C:16]([C:24]([OH:25])=[O:27])[CH:15]=[CH:14][C:13]1=2
Reactant: COc1ccccc1CCNC1CCCc2nc(C#N)ccc21
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(n1)CCCC2NCCc1ccccc1O
Temperature: 25 °C

Procedure:
14.6 g (47.5 mmol) of 5-{[2-(2-methoxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carbonitrile were taken up in 100 ml of hydrobromic acid (48% in water) and stirred at boiling point for 5 hours. The reaction solution was then cooled to room temperature, diluted with water and adjusted to pH 6 with saturated sodium bicarbonate solution. The crystals formed were filtered off with suction, washed with water and air-dried. This gave 14.6 g (46.76 mmol, 98% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([OH:22])(=[O:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].Cl.[CH2:39]([O:41][NH2:42])[CH3:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:42][O:41][CH2:39][CH3:40])(=[O:21])=[O:22])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: O=C(c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(Cl)ccc1Cl)N1CCC(c2ccc(F)cc2)CC1
Reactant: CCON
Agent: Cl
Product: CCONS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 21.9 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.15 g, 0.27 mmol) obtained in Example 27 step 1 and O-ethylhydroxylamine hydrochloride (0.104 g, 1.06 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.036 g, 22%) was obtained.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][CH3:30])=[CH:21][C:20]=1[CH2:31][CH2:32][CH2:33][C:34]#N.[OH2:36]>C(Cl)Cl>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][CH3:30])=[CH:21][C:20]=1[CH2:31][CH2:32][CH2:33][CH:34]=[O:36]
Reactant: COc1cc(CCCC#N)c(OC)c2ccccc12
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cc(CCCC=O)c(OC)c2ccccc12
Reaction time: 2 h

Procedure:
20 ml of a 1.0M hexane solution of diisobutylaluminum hydride were added at -70° C. to a solution of 3.36 g of 4-(1,4-dimethoxy-2-naphthyl)butyronitrile [prepared as described in step (a) above] in 100 ml of dry methylene chloride, and the resulting mixture was stirred for 2 hours. At the end of this time, water was added to the reaction mixture, and the insoluble materials were filtered off with the aid of a Celite (trade name) filter aid. The methylene chloride layer which separated was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give 2.96 g of the title compound as a colorless oil.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([C:10]2([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)C(C)C)(C)C.[Cl:45][C:46]1[C:54]([S:55]([NH:58][CH3:59])(=[O:57])=[O:56])=[CH:53][CH:52]=[C:51]([Cl:60])[C:47]=1[C:48](O)=[O:49].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:45][C:46]1[C:47]([C:48]([N:13]2[CH2:12][CH2:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)([CH2:16][CH2:17][N:18]3[CH:23]4[CH2:24][CH2:25][CH:19]3[CH2:20][CH:21]([N:26]3[C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[N:28]=[C:27]3[CH3:35])[CH2:22]4)[CH2:15][CH2:14]2)=[O:49])=[C:51]([Cl:60])[CH:52]=[CH:53][C:54]=1[S:55]([NH:58][CH3:59])(=[O:57])=[O:56]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 1-(8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (100 mg, 0.16 mmol, 1 equiv) and N,N-diisopropylethyl amine (117 μL, 0.66 mmol, 4 equiv) in dimethylformamide (2 mL) was added the mixture of 2,6-dichloro-3-[(methylamino)sulfonyl]benzoic acid 880-1 b. After stirring at RT for several min, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (62 mg, 0.16 mmol, 1 equiv) was added and the reaction was stirred for 18 h. The mixture was partitioned between dichloromethane and satd. aq. NaHCO3. The organic layer was dried and concentrated and the residue was purified by SiO2 flash column chromatography (100% EtOAc→10% 2M NH3 in MeOH in EtOAC) to provide 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide (example 880) as a white solid (25 mg, 22% yield).