Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[N:18]([C@@H:16]1[C@@H:15]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][N:13]([C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:12])[CH2:17]1)[CH3:19])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)Cl
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CCCCOC(=O)N(C)[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid butyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using butyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 510.4 [M]+.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:12]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=3)=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(Cc2cn(-c3ccccn3)c3cc(Cl)ccc3c2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2cn(-c3ccccn3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
A solution of 4-(7-chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-benzoic acid methyl ester (28 mg, 69.2 μmol) in tetrahydrofuran (553 μL) at 25° C. was treated with a solution of lithium hydroxide monohydrate (5.8 mg, 138 μmol) in water (138 μL). The reaction was stirred at 25° C. for 24 h. At this time, LCMS indicated that the reaction was incomplete. The reaction was treated with additional lithium hydroxide monohydrate (5.8 mg, 138 μmol). The reaction was stirred overnight at 25° C. At this time, LCMS still indicated that the reaction was incomplete. The reaction was treated with a third portion of lithium hydroxide monohydrate (5.8 mg, 138 μmol). The reaction was stirred overnight at 25° C. At this time, the reaction was diluted with water (30 mL) and extracted with methylene chloride (1×30 mL). The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution and extracted with a 10% solution of methanol/methylene chloride (3×50 mL). These organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-(7-chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-benzoic acid (18 mg, 66.6%) as a light brown solid. ES+-HRMS m/e calcd for C22H15ClN2O3 [M+H+] 391.0844. Found 391.0835; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.79 (br. s., 1H) 8.73 (dd, J=4.8, 1.2 Hz, 1H) 8.29 (s, 1H) 8.17-8.25 (m, 1H) 7.77-7.86 (m, 3H) 7.68 (dd, J=7.1, 5.2 Hz, 1H) 7.41-7.48 (m, 3H) 7.22 (d, J=1.8 Hz, 1H) 3.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]#[N:13])=[CH:5][NH:6]2.ClC1C=CC=C2C=1C=CN2.ClS([N:28]=[C:29]=[O:30])(=O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]#[N:13])=[CH:5][N:6]2[C:29]([NH2:28])=[O:30]
Reactant: N#CCc1c[nH]c2cccc(Cl)c12
Reactant: O=C=NS(=O)(=O)Cl
Agent: Clc1cccc2[nH]ccc12
Solvent: ClCCl
Product: N#CCc1cn(C(N)=O)c2cccc(Cl)c12
Reaction time: 1.5 h
Yield: 62 %

Procedure:
The (4-chloro-1H-indol-3-yl)-acetonitrile used in step 1 was prepared from commercially obtained 4-chloro-1H-indole (Aldrich Chemical Co. Cat. No. 24,622-0) using the procedure of steps 4 and 5 of Example 1. To (4-chloro-1H-indol-3-yl)-acetonitrile (500 mg, 2.62 mmol) dissolved in anhydrous dichloromethane (10 mL) was added chlorosulfonyl isocyanate (0.92 mL, 10.50 mmol). After 1.5 hours, the reaction was filtered and the resulting solid was washed with dichloromethane. The solid was then dissolved in acetone and water (2.5 mL) was added. The reaction mixture was concentrated to dryness to yield 4-Chloro-3-cyanomethyl-indole-1-carboxylic acid amide as a pale pink solid (377 mg, 62%). 1H NMR (DMSO-d6) δ: 4.27 (br s, 2H), 7.28 (m, 2H), 7.78 (br s, 2H), 7.98 (s, 1H), 8.28 (m, 1H); M+233.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[CH:9]3[CH2:10][C:11]4[CH:19]=[C:18]5[O:20][CH2:21][O:22][C:17]5=[CH:16][C:12]=4[CH2:13][C:14](=O)[N:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[CH:9]3[CH2:10][C:11]4[CH:19]=[C:18]5[O:20][CH2:21][O:22][C:17]5=[CH:16][C:12]=4[CH2:13][CH2:14][N:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN1C(=O)Cc3cc4c(cc3CC21)OCO4
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN1CCc3cc4c(cc3CC21)OCO4
Yield: 80 %

Procedure:
The title compound was prepared as described in Example 18 by the reduction of 5,9,15,15a-tetrahydro-3-methoxy-[1,3]dioxolo[4,5-h]isoquino-[1,2-b][3]benzazepine-8(6H)-one hemiethanolate (XIIb, Ex. 14) (3.60 g, 10 mmole) with deborane in tetrahydrofurane (25 ml of 1.0M solution). The product was extracted with methylene chloride. The methylene chloride extract was dried (Na2SO4), and evaporated on a rotary evaporator to give an oil which solidified on standing. Recrystallization from ethanol afforded the titled compound (2.57 g, 80%), mp 133°-135°.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[N:25][N:24]=[C:23]2[CH2:30][N:31]2C(=O)C3=CC=CC=C3C2=O)=[C:11]([CH:21]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=O)(=[O:6])=[O:5])([CH3:3])[CH3:2].O.NN>CO>[CH2:27]([C:26]1[N:22]2[C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:21][C:11]=3[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:31][CH2:30][C:23]2=[N:24][N:25]=1)[CH2:28][CH3:29]
Reactant: CCCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(S(=O)(=O)C(C)C)cc1C(=O)c1ccccc1F
Agent: NN
Solvent: O
Solvent: CO
Product: CCCc1nnc2n1-c1ccc(S(=O)(=O)C(C)C)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 5, a solution of 5-isopropylsulfonyl-2'-fluoro-2-[3-(phthalimidomethyl)-5-propyl-4H-1,2,4-triazol-4-yl]benzophenone in methanol was heated with hydrazine hydrate to give 1-propyl-8-isopropylsulfonyl-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[O:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23]C)=[O:22].[OH-].[Na+].Cl>C1COCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[O:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(COc2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 50 °C

Procedure:
A mixture of 1.6 g of methyl 3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoate and 0.5 g of NaOH in 20 ml of THF and 5 ml of H2O is heated at 50° C. overnight. The reaction mixture is acidified to pH 4 by 1N HCl solution, filtered and dried to give 3-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzoic acid. (M.P. 149°-151° C.)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][N:21]([C:36](=[O:37])[CH2:35][O:34][CH2:33][CH2:32][O:31][CH3:30])[CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: COCCOCC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)COCCOC)CC3)cc1

Procedure:
Compound ez was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea with 2-(2-methoxyethoxy)acetyl chloride. LC-MS: m/z=+513 (M+H)+.
Reaction SMILES: [C:1]1(=[O:13])[O:10][C:8](=O)[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22]C)=[O:20])=[CH:17][CH:16]=1.CC1(C)CC(=O)OC(=O)C1>>[CH3:3][C:2]12[C:4]([CH3:5])([CH3:6])[CH:7]([CH2:11][CH2:12]1)[C:8](=[O:10])[N:14]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:24][CH:25]=1)[C:1]2=[O:13]
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)C3CCC(C)(C2=O)C3(C)C)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and (+/−)-camphoric anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 19A. MS (DCI) m/e 333 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:3]3[C:2]([C:25]4[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=4)=[CH:7][N:6]=[CH:5][C:4]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1c(-c2nonc2N)nc2cncc(-c3ccc(C(=O)O)cc3)c21
Reaction time: 18 h
Yield: 35 %

Procedure:
To a solution of the product from Example 100 (1.5 g, 4.85 mmol) in 1,4-Dioxane (50 ml) was added 4-carboxybenzene boronic acid (1.20 g, 7.23 mmol), sodium carbonate (7 ml of a 2 M solution) and tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.97 mmol). The reaction mixture was heated to reflux with stirring for 18 hours and allowed to cool. The reaction mixture was filetered and washed with ether (5×, 100 ml) to afford the title compound as a yellow solid (0.594 g, 35%); MS (ES+) m/e 351 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:41]([OH:43])=[O:42])[CH2:24][C:25]4[CH:30]=[C:29]([CH3:31])[C:28]([O:32]CC5C=CC=CC=5)=[C:27]([CH3:40])[CH:26]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:44]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:41]([OH:43])=[O:42])[CH2:24][C:25]4[CH:26]=[C:27]([CH3:40])[C:28]([OH:32])=[C:29]([CH3:31])[CH:30]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:44]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)C(=O)O)CC1)C(=O)N2
Agent: [Pd]
Product: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(C)c(O)c(C)c3)C(=O)O)CC1)C(=O)N2

Procedure:
Prepared analogously to Example 21c from 0.64 g (1.06 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetra-hydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 100 mg 10% Pd/C.
Reaction SMILES: ClC1N=[N:6]C(NC)=C(C2C(OC)=NC=CC=2)C=1.[Cl:18][C:19]1[N:24]=[N:23][C:22]([N:25]([CH3:42])[C:26](=[O:41])[C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:28]=2)=[C:21]([C:43]2[CH:48]=[CH:47][C:46](F)=C[C:44]=2[O:50][CH3:51])[CH:20]=1>CCCCCCC.C(OCC)(=O)C>[Cl:18][C:19]1[N:24]=[N:23][C:22]([N:25]([CH3:42])[C:26](=[O:41])[C:27]2[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([S:37]([CH3:40])(=[O:38])=[O:39])[CH:28]=2)=[C:21]([C:43]2[C:44]([O:50][CH3:51])=[N:6][CH:46]=[CH:47][CH:48]=2)[CH:20]=1
Reactant: CNc1nnc(Cl)cc1-c1cccnc1OC
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 1, from [6-chloro-4-(2-methoxy-pyridin-3-yl)-pyridazin-3-yl]-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 1, intermediate d) after a reaction time of 27 hours and using a gradient of n-heptane:ethyl acetate (100:0 to 20:80) for the chromatographic purification. Light yellow solid (10%). MS (ESI+): m/z=501.060 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[C:5]=2[N:6]=1.[CH3:16][C:17]1[S:21][C:20]([C:22](Cl)=[O:23])=[CH:19][CH:18]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:14][C:12]([F:15])([F:13])[O:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:22]([C:20]3[S:21][C:17]([CH3:16])=[CH:18][CH:19]=3)=[O:23])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: Nc1nc2c(OC(F)(F)F)cccc2s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2nc3c(OC(F)(F)F)cccc3s2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
2-amino-4-triflouromethoxybenzothiazol (70 mg, 0.30 mmol) is dissolved in pyridine (3 ml) and treated with 4-dimethylaminopyridine (1 mg) and 5-methyl-thiophene-2-carbonyl chloride (96 mg, 0.60 mmol). After stirring for 4 h at ambient temperature, the reaction mixture was evaporated to dryness. Flash chromatography on silica (eluent ethyl acetate/cyclohexane 1:2) affords the product as white solid. (42 mg, 39% yield). MS: m/e=358 (M+).
Reaction SMILES: [F:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:25][CH3:26].[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:25][CH3:26])=[C:2]([F:1])[C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:15][CH:16]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1F
Product: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1F
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield from 7-fluoro-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part D) and 4-fluorobenzoyl chloride by essentially following the procedure outlined in Example 129, Part A.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[O:18].[I-].[K+].C(#N)C>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:17]([CH:13]1[CH2:14][CH2:15][CH2:16][O:12]1)=[O:18])=[O:5]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: O=C(OCCCCCCCCCl)C1CCCO1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(OCCCCCCCCOC(=O)C1CCCO1)c1cc(O)ccc1O

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (3.9 g), 1,8-diazobicyclo[5.5.0]undec-7-ene (3.8 g), 8-chlorooctyl tetrahydro-2-furancarboxylate (6.0 g), potassium iodide (30.2 g) and acetonitrile (110 ml) was heated, under reflux for 72 h. The cooled reaction mixture was added to water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×15 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuum. The residue (8.0 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (3:1) as eluent, to give 8-[(2,5-dihydroxybenzoyl)oxy]octyltetrahydro-2-furancarboxylate as colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[CH:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22](COCC[Si](C)(C)C)[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[CH:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:29][CH2:30]3)[C:11]=2[N:10]=1
Reactant: C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n[nH]c12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 30 ml round-bottomed flask equipped with a septum having a top-mounted argon intake is charged with 47 mg of 5-(2,6-difluorophenyl)-3-([1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-ethynyl-2H-pyrazolo[4,3-c]isoquinoline in 4 ml of DCM. After cooling to 0° C. using an ice bath, 0.47 ml of TFA is added and the mixture is stirred at RT for 3 h. It is concentrated under RP and the solid obtained is taken up in 25 ml of water and 0.75 ml of 0.75M aqueous ammonia solution. It is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and methanol (92.5/7.5 by vol.). This gives 6 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-7-ethynyl-2H-pyrazolo[4,3-c]isoquinoline (yellow solid). MS (E/1); m/z=481 (M+); 1H NMR: 1.66 (m, 2 H) 2.11 (m, 2 H) 2.87 (s, 3 H) 2.91 (m, 2 H) 3.56 (m, 2 H) 3.79 (m, 1 H) 4.37 (s, 1 H) 6.10 (d, J=8.3 Hz, 1 H) 7.34 (t, J=7.9 Hz, 2 H) 7.65 (broad s, 1 H) 7.69 (m, 1 H) 7.97 (broad d, J=8.3 Hz, 1 H) 8.42 (d, J=8.3 Hz, 1 H) 12.88 (broad s, 1 H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[C:34]([N:53]1[CH:57]=[CH:56][N:55]=[C:54]1[CH:58]=O)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2/[CH:12]=[CH:58]/[C:54]2[N:53]([C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:57]=[CH:56][N:55]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 321b) in THF (20 ml) was added sodium hydride (50% oil dispersion, 80 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. A solution of 1-trityl-1H-imidazole-2-carbaldehyde (367 mg) in THF (5 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give a crude product of the title compound as a pale-yellow solid (670 mg).
Reaction SMILES: [C:1]([CH:4]([C:14]1[N:22]2[C:17]([C:18](=[O:34])[NH:19][C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)=[N:21]2)=[C:16]([CH3:35])[N:15]=1)[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[CH:8]1([CH2:7][CH2:6][CH2:5][CH:4]([C:14]2[N:22]3[C:17]([C:18](=[O:34])[NH:19][C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[N:21]3)=[C:16]([CH3:35])[N:15]=2)[CH:1]([OH:3])[CH3:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(Cc2nn3c(C(CCCC4CCCCC4)C(C)=O)nc(C)c3c(=O)[nH]2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(Cc2nn3c(C(CCCC4CCCCC4)C(C)O)nc(C)c3c(=O)[nH]2)cc1OC

Procedure:
60 mg (0.13 mmol) of 7-(1-acetyl-4-cyclohexylbutyl)-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one are reacted analogously to Example 12 with 15 mg (0.40 mmol) of sodium borohydride to give 7-[4-cyclohexyl-1-(1-hydroxyethyl)butyl]-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: F[B-](F)(F)F.[N:6]1([O+]=C(N(C)C)N(C)C)[C:10]2C=CC=CC=2N=N1.CN.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:33]=[N:34][N:35]([C@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([C:49](O)=[O:50])[CH2:38]3)[CH:36]=2)=[CH:28][C:27]=1[C:52]1[O:53][C:54]2[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=2[N:56]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:33]=[N:34][N:35]([C@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:47])([CH3:48])[CH3:46])=[O:43])[C@H:39]([C:49](=[O:50])[NH:6][CH3:10])[CH2:38]3)[CH:36]=2)=[CH:28][C:27]=1[C:52]1[O:53][C:54]2[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=2[N:56]=1
Reactant: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)C[C@H]1C(=O)O
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A slurry of benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium tetrafluoroborate (149 mg) was added to methylamine (0.892 ml, 2M in methanol) and (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (175 mg) and triethylamine (0.883 ml) dissolved in DMF (8 ml) over a period of 10 minutes. The resulting solution was stirred at 25° C. overnight. The mixture was evaporated and a saturated solution of NaHCO3 (50 ml) was added to the mixture, extracted with methylene chloride (50 ml×2), dried over Magnesium sulphate, filtered and evaporated in reduce pressure. The reaction mixture was purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford (2S,4R)-tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-2-(methylcarbamoyl)pyrrolidine-1-carboxylate (60 mg) as a solid. Retention time: 3.44 min Mass spectrum: M+H+ 504