Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([CH3:18])[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:13]2[CH:14]=[CH:15][C:16]([OH:17])=[C:11]([CH3:18])[CH:12]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1O
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccc(Br)cc2)ccc1O
Temperature: 25 °C
Yield: 15.2 %

Procedure:
To a solution of 4-bromobenzoyl chloride (1.04 g, 4.74 mmol) and o-cresol (0.58 g, 5.33 mmol) in CH2Cl2 (20 mL) was added AlCl3 (0.76 g, 5.72 mmol) portion-wise. The mixture was allowed to warm to RT over 12 h. Water was added, and the mixture was extracted with CH2Cl2. The organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography on silica gel (EtOAc:hexanes) to yield 0.21 g (15%) of compound 32. 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 6.89 (d, J=8.3 Hz, 1H), 7.46 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.58 (d, 2H), 7.72 (d, 2H), 10.42 (s, 1H).
Reaction SMILES: [NH3:1].C(Cl)Cl.C1COCC1.Cl.[CH2:11]([NH2:14])[CH2:12][CH3:13].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:14][C:11]1[C:12]2[C:20](=[CH:19][CH:18]=[CH:17][CH:13]=2)[N:15]=[CH:16][N:1]=1.[NH3:14]
Reactant: CCCN
Reactant: c1ccncc1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1ncnc2ccccc12

Procedure:
To prepare the compound I-1, a 4-hydroxy-[1,5]-naphthyridine, a 4-hydroxyquinazoline, a 5-hydroxyquinoxaline or a 4-hydroxyquinoline derivative can be converted into the corresponding chloro derivative by heating in phosphorous oxychloride between 40° C. and 100° C. neat or in an inert solvent like 1,2-DCE, or to the corresponding trifluoromethanesulphonyloxy derivative by reaction with trifluoromethanesulphonic anhydride, in the presence of an organic base between −40° C. and 80° C. in an aprotic solvent like DCM or THF (K. Ritter, Synthesis (1993), 735). The corresponding 4-amino-[1,5]-naphthyridine, 4-aminoquinazoline, 5-aminoquinoxaline or 4-aminoquinoline derivatives can then be obtained by reaction of the corresponding trifluoromethanesulphonyloxy derivatives with ammonia in a solvent like DCM or THF, or with n-propylamine hydrochloride in pyridine between −20° C. and 100° C. (R. Radinov, Synthesis (1986), 886). The corresponding 4-aminoquinazoline can also be obtained from its 4-chloro analogue by reaction with ammonia under the same conditions.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:11][C@H:10]2[NH2:12])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[F:18][CH:19]([F:29])[C:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]([CH3:28])[N:21]=1.CCOC(C)=O.CCCCCC>ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@H:10]2[NH:12][C:25]([C:24]2[C:20]([CH:19]([F:29])[F:18])=[N:21][N:22]([CH3:28])[CH:23]=2)=[O:26])=[CH:7][CH:8]=1
Reactant: N[C@@H]1C[C@@H]1c1ccc(F)cc1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cn1cc(C(=O)N[C@@H]2C[C@@H]2c2ccc(F)cc2)c(C(F)F)n1
Yield: 85.3 %

Procedure:
cis-2-(4-Fluoro-phenyl)-cyclopropylamine hydrochloride (0.153 g, 0.815 mmol) was dissolved in dichloromethane (4.5 ml) and stirred with NaHCO3 (1 M, 4.5 ml). 3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carbonyl chloride (0.190 g, 0.978 mmol) was added dropwise. After three hours rapid stirring tlc (50% EtOAc/hexane) showed the reaction to be finished. The mixture was separated between dichloromethane and water, washed with NaCl (sat), dried (MgSO4), and evaporated to yield 245 mg of nearly pure product, which was washed with cyclohexane to yield 215 mg (85%) of the product as a white solid m.p. 141-143° C.
Reaction SMILES: C(O[C:5](=[O:33])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH2:13][C:14](=[O:32])[NH:15][C:16]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27]C=[C:25]([CH2:29][F:30])[CH:24]=4)[C:20](C)=[CH:19][C:17]=3[N:18]=2)[CH:7]=1)C=C.O.[NH2:35][NH2:36]>CO.O>[F:30][C:29]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:12]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[C:5]([NH:35][NH2:36])=[O:33])[CH2:13][C:14](=[O:32])[NH:15][C:16]=3[CH:22]=2)=[CH:24][CH:25]=1
Reactant: NN
Reactant: C=CCOC(=O)c1cccc(C2=Nc3cc(C)c(-c4cccc(CF)c4)cc3NC(=O)C2)c1
Solvent: O
Solvent: CO
Product: NNC(=O)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
To a suspension of 3-[7-(3-fluoromethyl-phenyl)-8-methyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid allyl ester (Starting material 8a-1) (207 mg, 0.5 mmol) in MeOH (3.5 mL) was added hydrazine hydrate (0.25 mL, 5 mmol). The mixture was stirred at 60° C. for 15 h, then cooled to 23° C. and diluted with H2O (35 mL). The precipitate was collected by filtration and dried, and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (1:1) as eluent. The purified product was crystallized from Et2O/hexane to give the title compound as light yellow solid (64 mg).
Reaction SMILES: [NH2:1][C@:2]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:43])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH2:42][C:26]4([CH2:29][C:28]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:27]4)[CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.C(O)(=O)C.[H][H]>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:1][C@:2]12[CH2:46][CH2:45][C@@H:44]([CH:47]([CH3:49])[CH3:48])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:43])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:22])([CH3:23])[C:11]([CH:24]2[CH2:25][C:26]4([CH2:29][C:28]([C:30]([O:32][CH:33]([CH3:34])[CH3:35])=[O:31])([C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])[CH2:27]4)[CH2:42]2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC2(CC(C3=CC[C@]4(C)[C@H]5CC[C@@H]6[C@H]7[C@H](C(C)C)CC[C@]7(N)CC[C@@]6(C)[C@]5(C)CC[C@H]4C3(C)C)C2)C1
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (0.057 g, 0.085 mmol) in ethanol (2 mL), 1,4-dioxane (2 mL) and acetic acid (0.02 mL, 0.349 mmol) was added palladium hydroxide (20% on carbon) (0.072 g, 0.103 mmol). The mixture as stirred under 1 atm of hydrogen overnight. After stirring the mixture for 15 h, it was filtered through a plug of celite (washed with MeOH) then the filtrate was concentrated under reduced pressure. The residue was diluted with 15 mL of sat. aq. NaHCO3 and extracted with dichloromethane (3×15 mL). The combined organic layers were dried with sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give diisopropyl 6-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]heptane-2,2-dicarboxylate (0.057 g, 0.085 mmol, 100% yield) as an off-white solid. 1H NMR (500 MHz, chloroform-d) δ=5.33 (d, J=5.7 Hz, 1H), 5.11-5.02 (m, 2H), 3.80-3.72 (m, 1H), 3.68-3.60 (m, 1H), 2.66 (s, 2H), 2.44 (s, 2H), 2.99-0.64 (m, 62H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C:35]([F:38])([F:37])[CH2:34][CH2:33][C@@H:32]2[C:39]2[N:43](COCCOC)[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C:35]([F:38])([F:37])[CH2:34][CH2:33][C@@H:32]2[C:39]2[NH:43][N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COCCOCn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1Cl
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@H]2CC(F)(F)CC[C@@H]2c2ccn[nH]2)cc1F
Yield: 41 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 155i by using the 5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (105 mg, 0.145 mmol) prepared in Example 156a, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL), dichloromethane (3.0 mL), 6 M hydrochloric acid (5.0 mL) and methanol (15 mL), to yield the title compound (29 mg, 41%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4(O)[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]([C:34]5[CH:39]=[CH:38][C:37]([C:40]6[CH:45]=[CH:44][CH:43]=[C:42]([C:46]7[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=7)[CH:41]=6)=[CH:36][CH:35]=5)(O)[C:25]5[C:20]4=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:32]5[C:27]([C:26]([C:34]6[CH:39]=[CH:38][C:37]([C:40]7[CH:45]=[CH:44][CH:43]=[C:42]([C:46]8[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=8)[CH:41]=7)=[CH:36][CH:35]=6)=[C:25]6[C:20]=4[CH:21]=[CH:22][CH:23]=[CH:24]6)=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccc(-c3cccc(-c4ccccc4)c3)cc2)c2ccccc2C(O)(c2ccc(-c3cccc(-c4ccccc4)c3)cc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2cccc(-c3ccc(-c4c5ccccc5c(-c5ccc(-c6cccc(-c7ccccc7)c6)cc5)c5ccccc45)cc3)c2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
9,10-bis(4-(3-Phenylphenyl)phenyl)-9,10-dihydroxy-9,10-dihydro-anthracene (4.9 g, 7.3 mmole) was suspended in acetic acid (70 ml). To the resultant suspension, a 57% hydroiodic acid (10 ml, 77 mmole, 10 eq) was added and the obtained mixture was stirred at 100° C. for 6 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (50 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a light yellow solid (4.1 g, 79%) was obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:11][N:10]=[CH:9][CH:8]=1.[Li].[Li+].CC([N-]C(C)C)C.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>CCCCCC.C1COCC1>[C:7]([CH:8]([C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:25])[C:9]#[N:10])(=[O:11])[CH3:6]
Reactant: Cc1ccno1
Reactant: O=C(Cl)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)C(C#N)C(=O)C1CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
n-Buyllithium (19.44 ml, 52.5 mmole of a 2.7 M solution in hexane) was added at -15° C. to a solution of diisopropylalmine (5.31g, 52.5 mmole) in 80 ml of dry THF. After 10 min the cooling bath was lowered to -70° C. and 5-methylisoxazole (4.15 g, 50 mmoles) was added to the lithium diidopropylalmine (LDA) solution followed in 30 min by the dropwise addition of cyclopropanecarboxylic acid chloride (5.33 g, 50 mmoles) in 15 ml of THF. The reaction mixture was then stirred at -78° C. for 30 min and at ambient temperature for 2 h. The solvents were evaporated and the residue was partitioned between ether, 30 ml of water and 13 ml of 4 N NaOH. The aqueous layer was separated, acidified with 6 N HCl and extracted with two portions of ether. The extracts were dried and evaporated to a slushy solid that was cchromatographed on 100 g of silica gel using methylene chloride-Skellysolve B (95:5). The appropriate fractions were combined and concentrated to yield 2.26 g of the title compound as a yellow-tinted solid, mp 62°-63.5° C.
Reaction SMILES: C([BH3-])#N.[Na+].S(O)(O)(=O)=O.[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH:17]([NH2:22])[CH2:16]2)([O-:12])=[O:11].[O:23]([CH2:31][CH:32]=O)[Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(=O)(O)[O-].[Na+]>CO>[Si:24]([O:23][CH2:31][CH2:32][NH:22][CH:17]1[CH2:16][C:15]2[C:19](=[CH:20][CH:21]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[CH2:18]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
0.91 g of sodium cyanoborohydride was added to a methanol (100 mL) solution of 2 g of 5-nitroindan-2-amine sulfate and 1.9 g of (tert-butyldimethylsiloxy)acetaldehyde, and stirred at room temperature for 2 days. The reaction liquid was neutralized with aqueous saturated sodium bicarbonate solution, and methanol was evaporated away under reduced pressure. The residue was diluted with water, and extracted three times with chloroform. The organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and the crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 1.56 g of the entitled compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][C:10]3(OCC[O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1

Procedure:
A mixture of 2-[2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]-1H-isoindole-1,3(2H)-dione (7-2) (3.1 g, 7.48 mmol) and p-toluenesulfonic acid monohydrate (0.14 g, 0.75 mmol) in acetone (50 mL) was refluxed for 2 days. The cooled mixture was diluted with EtOAc, washed with sat. NaHCO3, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0˜100% EtOAc in hexane, to give 2-[1-(4-bromophenyl)-3-oxocyclobutyl]-1H-isoindole-1,3(2H)-dione (7-3) as a colorless form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NC1CCCC1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and cyclopentylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C.O.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-nitro-3,4-dihydroquinolin-2(1H)-one (0.5 g, 2.6 mmol) and Cs2CO3 (1.70 g, 5.2 mmol) in DMF (5 mL) was added ethyl 2-bromoacetate (0.317 mL, 2.86 mmol). After stirring at 65° C. for 3 h, the mixture was diluted with H2O and EtOAc, organic layer was separated, and the aqueous layer was further extracted with EtOAc, organic layers were combined, dried over Na2SO4, and was concentrated in vacuo to provide ethyl 2-(6-nitro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate, which was used directly for next step.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[C:9]([F:17])[CH:8]=1.O=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1>[F:17][C:9]1[CH:8]=[C:7]([C:19]2[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:22][CH:23]=2)[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Fc1cc(Br)c2c(c1)OCCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC=C1c1cc(F)cc2c1OCCO2
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of isopropyl magnesium chloride in THF (2M, 5.39 mL, 10.78 mmol) was added to a solution of 5-bromo-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (Int-53) (1 g, 4.31 mmol) in THF (10 mL) at −45° C. drop-wise and then allowed it to warm up to 5° C. over a period of 1 h. The reaction mixture was cooled again to −45° C. and a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.6 g, 8.62 mmol) in THF (10 mL) was added drop-wise maintaining the temperature at −45° C. The reaction mixture was warmed to 25° C. and stirred for 1 h and then quenched with saturated NH4Cl solution (100 mL). The reaction mixture was extracted with ethyl acetate (3×30 mL) and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure and purified by column chromatography (using silica gel and 20% ethyl acetate Hexane as eluent) to afford tert-butyl 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (Int-54). MS (ESI) m/z 340 (M−+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].B(O)(O)O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: Nc1ccccc1S
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: c1c[nH]c(-c2nc3ccccc3s2)c1
Yield: 14 %

Procedure:
A mixture of 5.55 g (50 mmol) of pyrrole-2-carboxylic acid, 6.26 g (50 mmol) of 2-aminothiophenol and 3.09 g (50 mmol) of boric acid in 250 mL of xylene was heated under reflux for 3 days while removing water which was generated from reaction using a Dean-Stark trap. the cooled reaction mixture was diluted with 200 mL of ethyl acetate, washed with 200 mL of 5% sodium hydroxide solution and then with 200 mL of water. The separated organic layer was dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography on silica gel with 10% ethyl acetate in hexane as eluant. The desired product, 2-(pyrrol-2-yl)benzothiazole (1.40 g, 14%) was obtained as a pale yellow solid. m.p. 150°-151° C.; 1H-NMR (CDCl3) 6.32-6.35 (m, 1H, ArH), 6.87-6.89 (m, 1H, ArH), 6.94-6.96 (m, 1H, ArH), 6.33 (t, 1H, ArH), 6.43 (t, 1H, ArH), 7.84 (d, 1H, ArH), 7.90 (d, 1H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:20])[C:12]1([C:17](O)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17]([C:12]2([N:11]([CH3:20])[CH3:10])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:18])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN(C)C1(C(=O)O)CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C1(C(=O)NNc2ccc(F)cn2)CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 200 mg, 1.57 mmol) in DMF (10 mL) were added Intermediate 99a (247 mg, 1.57 mmol), EDC (333 mg, 1.73 mmol) and HOBt (21 mg, 0.16 mmol). The reaction mixture was stirred at RT for 18 h and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-8% (2M NH3 in MeOH) in DCM, to give the title compound (282 mg, 67%). 1H NMR (400 MHz, CDCl3): 1.54-1.73 (4H, m), 1.76-2.04 (4H, m), 2.25 (6H, s), 6.46 (1H, s), 6.64 (1H, dd, J=9.0, 3.5 Hz), 7.23-7.33 (1H, m), 8.04 (1H, d, J=−3.0 Hz), 8.94 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([OH:21])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].[Br:22]Br.O>C(O)(=O)C>[Br:22][C:15]1[C:4]2[S:5][C:6]([C:7]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[O:8])=[C:2]([Cl:1])[C:3]=2[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[OH:21]
Reactant: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2cc1O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1O

Procedure:
(3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (6.9 g) was slurried in acetic acid. A solution of bromine (3.51 g) in acetic acid (31 ml) was gradually added. The reaction mixture was stirred at room temperature and after 15 minutes water (125 ml) was added. The reaction mixture was stirred at cool for 1.5 hours. The solid was filtered and dried in vacuum. The product was a mixture of two compounds and was used for the next step without any purification.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.C[O:29][C:30](=O)[CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1>>[OH:38][C@H:35]1[CH2:36][CH2:37][C@H:32]([CH2:31][C:30]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH:6]=[CH:5][S:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:29])[CH2:33][CH2:34]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Reactant: COC(=O)C[C@H]1CC[C@H](O)CC1
Agent: Cl
Product: O=C(C[C@H]1CC[C@H](O)CC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 2 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (1150 mg, 0.33 mmol) and trans-(4-hydroxy-cyclohexyl)-acetic acid methyl ester [CAS-Nr. 1124174-16-8, WO 2010/031735] (68 mg, 0.39 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (83 mg, 52%), MS (ISP) m/z=485.4 [(M+H)+].