Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:10][CH:9]=1)(C)(C)C.Cl.C([O-])(O)=O.[Na+].[Br:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1>CCOC(C)=O.C(Cl)Cl>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:26])[CH3:27])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:12][CH:13]=2)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:49])([F:48])[F:50])[CH:37]=1
Reactant: CN(C)c1nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1nc(Nc2ccc(NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)cc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
To a suspension of [4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (380 mg, 1.00 mmol) in EtOAc (4 mL) and CH2Cl2 (4 mL) was added 4 M hydrogen chloride in EtOAc (4 mL). The mixture was stirred at ambient temperature for 4 hr and concentrated to give a white solid. The solid was alkalized with saturated aqueous NaHCO3 filtered, washed with H2O and hexane, and dried at 50° C. under reduced pressure. To a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (680 mg, 2.00 mmol) in CH2Cl2 (30 mL) was added PVP (8 mL). To the resulting suspension was added a solution of the above solid in CH2Cl2 (5 mL). The mixture was stirred at ambient temperature for 10.5 hr and filtered. The filtrate was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, EtOAc) to give a solid. The solid was washed with Et2O and dried at 50° C. under reduced pressure to give 4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-2-trifluoromethoxy-benzenesulfonamide (202 mg, 35%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[C:5]([CH3:11])[C:4]=1[CH3:12])#[N:2].[ClH:13]>CO.[Pd]>[ClH:13].[NH2:2][CH2:1][C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: Cc1c(C#N)sc(C(N)=O)c1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(CN)sc(C(N)=O)c1C

Procedure:
19 g (105.42 mmol) of 5-cyano-3,4-dimethylthiophene-2-carboxamide were suspended in 760 ml of methanol and 110 ml of 2N hydrochloric acid solution and, after addition of 9.5 g of Pd on carbon (10%), hydrogenated at room temperature. After uptake of 4.7 l of hydrogen (4 h), methanol was distilled out in vacuo, and the aqueous phase was extracted three times with ethyl acetate and then freeze dried. 16.3 g of the required product were obtained as a white solid (70.4% of theory).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH:22]=1>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Reactant: O=C(O)CCCCc1cccnc1
Product: O=C(CCCCc1cccnc1)N1CCC(C=C(c2ccccc2)c2ccccc2)CC1
Yield: 94.2 %

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of example 10 starting with 5.27 g of 4-(2,2-diphenylethenyl)piperidine and the acid chloride prepared from 6.5 g of 3-pyridine pentanoic acid. The toluene extracts were evaporated and chromatographed on a Waters Prep 500 using silica gel columns and eluting with 98:2 ethyl acetate-triethylamine. Evaporation of the combined product fractions gave 8.0 g (94%) of crude 4-(2,2-diphenylethenyl)-1-[1-oxo-5-(3-pyridinyl)pentyl]piperidine. Crystallization of a small portion from ether gave analytically pure 4-(2,2-diphenylethenyl)-1-[1-oxo-5-(3-pyridinyl)pentyl]piperidine, mp 82°-84° C. Analysis Calculated for C29H32N2O: C, 82.04; H, 7.60; N, 6.60. Found: C, 81.88; H, 7.63; N, 6.67.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:40]([C:37]1[CH:36]=[CH:35][C:34]([CH:28]([O:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CCCCCC(Br)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC(Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.1 %

Procedure:
A mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butyrate (176 mg), 1-(1-bromohexyl}-4-isobutylbenzene (223 mg) and potassium carbonate (207 mg) in N,N-dimethylformamide (4 ml) was stirred at room temperature for 6 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (3:1) to give ethyl 4-[3-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol-1-yl]-butyrate (279 mg) as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@H:31]([NH2:36])[CH2:32][N:33]([CH3:35])[CH3:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@H:31]([NH:36][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:32][N:33]([CH3:34])[CH3:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CCCCCCCCCc1ccccc1
Reactant: CN(C)C[C@@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Product: CN(C)C[C@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=377.5 ([M+H]+), was produced in analogy with example 1, steps 3 and 4. Thus, commercially available 10-phenyldecanoic acid was coupled in step 3 with (S)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (S)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15]Br)=[CH:11][CH:10]=1)C1C=CC=CC=1.[ClH:19].[F:20][C:21]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:22]=1[CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:27]2[CH2:26][CH2:25][CH:24]([CH2:23][C:22]3[C:21]([F:20])=[CH:33][CH:32]=[CH:31][C:30]=3[F:34])[CH2:29][CH2:28]2)=[CH:17][CH:18]=1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Reactant: Fc1cccc(F)c1CC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccc(OCCN2CCC(Cc3c(F)cccc3F)CC2)cc1

Procedure:
The title compound was prepared from 2-(4-benzyloxyphenoxy)ethyl bromide (0.393 g, 1.28 mmol), 4-(2,6-difluorobenzyl)piperidine hydrochloride (0.317 g, 1.28 mmol) and potassium carbonate (0.444 g, 3.2 mmol) in two steps as off white solid (0.240 g). mp 198-200° C. 1H NMR (CD3OD) 1.595 (m, 2 H), 1.906 (m, 3 H), 2.705 (d, J=5.7 Hz, 2 H), 3.029 (t, J=12.3 Hz, 2 H), 3.303 (m, 2 H), 3.629 (d, J=12.6 Hz, 2 H), 4.238 (t, J=4.5 Hz, 2 H), 6.702 (d, J=9.0 Hz, 2 H), 6.825 (d, J=9.0 Hz, 2 H), 6.953 (m, 2 H), 7.277 (m, 1 H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)([CH3:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: O=C(O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(C)OC(=O)CCc1ccccc1
Yield: 94 %

Procedure:
To a mixture of 3-phenylpropionic acid (15.0 g) and isopropanol (6.61 g) in pyridine (30 ml) perchloric acid (0.150 g) and DCC (24.8 g) are added. After stirring at room temperature for 24 h acetic acid (10 ml) is added, and the reaction mixture is worked-up as described in Example 1 to give a 94% yield of isopropyl 3-phenylpropionate (b. p., see Example 2).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7](#[N:10])[CH2:8]O.CCOCC>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:8][C:7]#[N:10])[CH3:6]
Reactant: CNCCOC
Reactant: N#CCO
Solvent: O
Solvent: CCOCC
Product: COCCN(C)CC#N
Temperature: 70 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
2-Methoxy-N-methylethanamine 266 (10.0 g, 112 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 12.0 mL, 123 mmol) at 0° C. and the mixture stirred at 70° C. for 1 h. The solution was cooled to 20° C., and Et2O (150 mL) and water (100 mL) were added. The aqueous layer was extracted with Et2O (3×40 mL), the combined organic fraction dried and the solvent evaporated to give nitrile 267 (6.46 g, 45%) as a colourless oil: 1H NMR [(CD3)2SO] δ 3.63 (s, 2H, CH2CN), 3.50 (t, J=5.1 Hz, 2H, CH2O), 3.37 (s, 3H, OCH3), 2.69 (t, J=5.1 Hz, 2H, CH2N), 2.42 (s, 3H, NCH3); HRMS calcd for C6H12N2O (M+) m/z 128.0947, found 128.0946.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:25]2[CH2:26][CH2:27][N:28]([C:10]([C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)=[O:12])[CH2:29][CH2:30]2)=[O:24])=[CH:21][CH:22]=1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Yield: 14.6 %

Procedure:
Using 4-methanesulfonylaminobenzoic acid (136 mg) and (4-methylphenyl)(piperidin-4-yl)methanone hydrochloride (152 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (37 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCCC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 7-(2,6-dimethoxyphenyl)azepan-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.98 min.; [M+H]+: 424.20 g/mol.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][C:33]1[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][O:36][C:37]=1[CH3:38]>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[CH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20](=[O:27])(=[O:28])[N:19]1[CH2:32][C:33]1[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][O:36][C:37]=1[CH3:38]
Reactant: Cc1onc(-c2ccccc2)c1CCl
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: Cc1onc(-c2ccccc2)c1CN1C(c2c(C)n(CC(=O)O)c3ccc(Cl)cc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 6, step c) and 4-chloromethyl-5-methyl-3-phenyl-isoxazole. 1H NMR (DMSO-d6) 7.99-7.91 (m, 1H), 7.69-7.60 (m, 2H), 7.43 (d, J=8.7 Hz, 1H), 7.36 (d, J=7.2 Hz, 2H), 7.23-6.75 (m, 6H), 5.94 (s, 1H), 4.96 (s, 2H), 4.33 (d, J=14.1 Hz, 1H), 4.07 (d, J=14.1 Hz, 1H), 3.30 (s, 3H), 2.41 (s, 3H); MS: ESI (negative): 560, 562 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[N:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(Cc2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzyl-6-bromo-pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:49]=[CH:48][C:5]([C:6]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([S:18]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)(=[O:20])=[O:19])[CH:16]=3)[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=2)=[O:7])=[C:4]([N:50]([CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)C(=O)C(F)(F)F)[CH:3]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[CH3:88][N:89]([CH3:94])[CH2:90][C:91](=O)[CH3:92]>ClCCl>[F:27][C:25]1[CH:26]=[C:21]([S:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[NH:8][C:6](=[O:7])[C:5]2[CH:48]=[CH:49][C:2]([NH:1][CH:91]([CH3:92])[CH2:90][N:89]([CH3:94])[CH3:88])=[CH:3][C:4]=2[NH:50][CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)(=[O:19])=[O:20])[CH:22]=[C:23]([F:28])[CH:24]=1
Reactant: CC(=O)CN(C)C
Reactant: Nc1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CN(C)C)Nc1ccc(C(=O)Nc2n[nH]c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide (1.56 g, 1.8 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (2.78 mL, 36 mmol), tetramethylammonium triacetoxyborohydride (710 mg, 2.7 mmol) and 1-dimethylamino-propan-2-one (316 microL, 2.7 mmol). The mixture was stirred at room temperature overnight then additional tetramethylammonium triacetoxyborohydride (710 mg, 2.7 mmol) and 1-dimethylamino-propan-2-one (316 microL, 2.7 mmol) were added. The mixture was heated at reflux and stirred for additional 6 hours. After evaporation of the volatiles, the residue was chromatographed on silica gel eluting with dichloromethane/methanol/triethylamine 90:10:0.1 affording 845 mg of N-[5-(3,5-difluoro-benzenesulfonyl)-1H-indazol-3-yl]-4-(2-dimethylamino-1-methyl-ethylamino)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide that was dissolved in methanol (5 mL) and triethylamine (2 mL) and stirred at 50° C. for 6 hours. The mixture was then evaporated to dryness and the residue purified by flash chromatography on silica gel eluting with dichloromethane/methanol/30% NH4OH 92:8:0.5 affording 416 mg of the title compound as pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[C:8](=[O:14])[C:7]=2[C:6]([CH3:15])=[CH:5][C:4]=1[CH3:16].Br.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[C:8](=[O:14])[C:7]=2[C:6]([CH3:15])=[CH:5][C:4]=1[CH3:16]
Reactant: COc1c(C)cc(C)c2c1OC(C)(C)C2=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(c1O)OC(C)(C)C2=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
A mixture of 7-methoxy-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (1.10 g, 4.99 mmol) synthesized in Reference Example 68, 48% hydrobromic acid (20 mL) and acetic acid (4 mL) was stirred at 100° C. for 15 hours. The reaction solution was poured into cold saturated sodium bicarbonate water in ice bath and extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 95:5 to 80/20) to give 980 mg of the title compound (yield: 95%).
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5](O)[C:4]=2[N:3]=[CH:2]1.P(Cl)(Cl)([Cl:17])=O.[OH-].[NH4+]>CN(C)C=O>[Cl:17][C:5]1[C:4]2[N:3]=[CH:2][NH:1][C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2c2[nH]cnc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2c2[nH]cnc12

Procedure:
To a mixture of 7.7 g (0.0416 mole) of 1H-imidazo[4,5-c]quinolin-4-ol and 50 mL of N,N-dimethylformamide was added in small portions 12 mL (0.13 mole) of phosphorus oxychloride. The mixture was heated on a steam bath for 1.5 hour, poured onto ice and basified with concentrated ammonium hydroxide. The solid precipitate was separated by filtration, washed with water and dried to provide 4-chloro-1H-imidazo[4,5-c]quinoline as a tan powder corresponding to the product of Example 30.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:31][CH2:32][Cl:33])(=O)=O)=CC=1>C(C(C)=O)C>[Cl:33][CH2:32][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COC(=O)C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C1CCc2cc(OCCCl)ccc21
Reaction time: 0.5 h

Procedure:
In a 20-liter reactor provided with a mechanical stirrer and reflux cooler, 1078 g of methyl 2,3-dihydro-5-hydroxy-1H-inden-1-carboxylate were dissolved with 9 l of dry methyl ethyl ketone, 1162 g of anhydrous potassium carbonate were added and stirred for 30 minutes; then 1448 h of 2-chloroethyl p-toluensulphonate were added and refluxed in oil bath for 50 hours. The mixture was allowed to cool, the insoluble solid was filtered and washed twice with acetone over the same filter. The filtrate was evaporated and dried at vacuum, the residue was dissolved in 4.7 l of toluene and extracted with 1.8 l of 3N sodium hydroxyde solution through the decantation funnel and mechanical stirring for 15 minutes; then it was neutralized with water and dried. After evaporation of solvent at vacuum, the residue as reddish liquid weighed 1419 g (99%). Thin-layer chromatography (silica-gel) showed a major spot and a slight shadow at lower Rf. Cl analysis correct. It was used for the following synthesis step without further purification.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]1[CH2:14][C:13]2[C:8]3=[C:9]([N:15]([O:18][CH3:19])[C:16](=[O:17])[N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3].I[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C@@H:5]1[CH2:14][C:13]2[C:8]3=[C:9]([N:15]([O:18][CH3:19])[C:16](=[O:17])[N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: CCCN[C@@H]1Cc2cccc3c2n(c(=O)n3OC)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CCC)[C@@H]1Cc2cccc3c2n(c(=O)n3OC)C1
Yield: 80.5 %

Procedure:
Following the procedure of Example 3, a mixture of (R)-5-Propylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (8b, 0.93 g, 3.56 mmol) 1-iodopropane (3.05 g, 17.9 mmol), and potassium carbonate (1.97 g, 14.3 mmol) in acetonitrile (25 ml) was heated at reflux under nitrogen for 17 hours. 1-Iodopropane (3.05 g, 17.9 mmol) was again added, and the mixture was refluxed for an additional 5 hours. The solvent was removed under vacuum, and the mixture was diluted with water and extracted twice with diethylether. The organic extract was washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave an amber oil. Purification by flash chromatography (230-400 mesh silica gel; 10-25% ethyl acetate in hexane) gave the title compound (9b) as an amber oil (0.87 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].[CH2:13]([CH2:15][NH2:16])[OH:14].CCN(CC)CC>CCO>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:16][CH2:15][CH2:13][OH:14]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1NCCO

Procedure:
2-Chloro-1,3-difluoro-4-nitrobenzene (5.37 g, 27.7 mmol), ethanolamine (1.69 g, 27.7 mmol) and Et3N (2.80 g, 27.7 mmol) are stirred in EtOH (40.0 mL) at room temperature for 2 hours. The solvent is then evaporated, and the resulting residue is suspended in EtOAc (50.0 mL) and washed with 0.5 N NaOH (50.0 mL). The aqueous phase is extracted 4 times with EtOAc (4×50.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated. The product is purified by flash chromatography on silica gel, eluting with mixtures of heptane and EtOAc (5.53 g, 85%). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.39 (dd, J=10.55, 5.27 Hz, 2H) 3.53 (t, J=5.47 Hz, 2H) 4.89 (s, 1H) 6.89 (dd, J=9.37, 8.01 Hz, 1H) 7.19 (t, J=4.69 Hz, 1H) 8.01 (dd, J=9.47, 5.96 Hz, 1H).