Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[CH:15][NH:16]3)[CH:6]=1>O1CCCC1>[NH2:3][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[CH:15][NH:16]3)[CH:6]=1
Reactant: N
Reactant: Clc1cc(Nc2cccc3[nH]ccc23)ncn1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Nc2cccc3[nH]ccc23)ncn1
Temperature: 130 °C
Yield: 82 %

Procedure:
A 7N methanol solution of ammonia (50 ml) and tetrahydrofuran (20 ml) were added to 6-chloro-4-(1H-4-indolylamino)pyrimidine (599 mg, 2.5 mmol) and the reaction mixture was heated in a sealed tube at 130° C. for 137 hours. The solvent was distilled off under reduced pressure; the residue was purified by silica gel column chromatography (eluent; ethyl acetate:tetrahydrofuran=1:1); diethyl ether was added to the residue to crystallize; the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (454 mg, 2.0 mmol, 82%) as pale brown crystals.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([Cl:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:16]=2[F:33])[CH2:10]1)=O)(C)(C)C>CO.Cl>[NH2:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([Cl:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:16]=2[F:33])[CH2:10]1
Reactant: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
7-(3-t-Butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.35 g) was dissolved in the mixture of methanol (5 ml) and concentrated hydrochloric acid (5 ml) and stirred at room temperature for 30 minutes. After the reacting mixture was concentrated under reduced pressure, the resulting residue was dissolved in ethanol (10 ml) and neutralized with concentrated aqueous ammonia. The resulting precipitate was collected by filtration, washed with water and recrystallized from chloroformmethanol-concentrated aqueous ammonia to give the title compound (0.07 g) as pale yellow powder, mp 231°-234° C.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:41])([CH:39]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH3:38])[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([S:8][C:9]([CH3:41])([CH2:39][N:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH3:38])[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:30])=[O:31])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(C=O)SCc3ccccc3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(CN3CCSCC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a mixture of N-[2-(benzylthio)-2-methyl-3-oxopropyl]-5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (1.56 g) and 1,2-dichloroethane (50 mL) was added thiomorpholine (1.31 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.66 g) was added, and the reaction mixture was stirred overnight at room temperature. Aqueous sodium bicarbonate was added, and the mixture was extracted with 1,2-dichloroethane. The extract was washed with saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (998 mg, yield 56%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[C:5]([CH3:9])=[CH:4][N:3]=1.[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[C:11]1=2.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1COCC1>[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[C:18]([C:6]3[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([F:1])[CH:7]=3)[C:11]1=2
Reactant: CC1(C)OB(c2cccc3ccsc23)OC1(C)C
Reactant: Cc1cnc(F)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cnc(F)cc1-c1cccc2ccsc12
Temperature: 100 °C
Yield: 82.2 %

Procedure:
In a flask, combine 2-fluoro-4-iodo-5-methyl-pyridine (355 mg, 1.5 mmol), 2-benzo[b]thiophen-7-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (282 mg, 1.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (61 mg, 0.07 mmol), 2-(di-tert-butylphosphino)biphenyl (13 mg, 0.04 mmol), sodium carbonate (2 M, 1.5 mL, 3 mmol) and THF (10 mL). Heat the mixture at 100° C. for 3 hours in an oil bath. Dilute the mixture with chloroform/isopropanol (3/1). Wash the solution with saturated aqueous sodium chloride. Dry over sodium sulfate. Concentrate in vacuo to a dark residue. Purify by column chromatography (20% ethyl acetate in hexane) to afford the title compound (300 mg, 82%) as yellow oil. MS (ES) m/z 244 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:28][C:25]2[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 4-trifluoromethyl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)C)(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:27]1[CH:28]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:6])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH:24]=[N:25][CH:26]=1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2cncc(F)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3cncc(F)c3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(5-fluoro-pyridin-3-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(5-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 52%.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[CH:3][C:2]=1[C:6]([NH:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[S:5]1[CH:4]=[CH:3][C:2]([CH2:6][NH:8][C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[NH:11][CH:12]=[N:13]3)=[CH:1]1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccsc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: c1nc(NCc2ccsc2)c2[nH]cnc2n1
Reaction time: 3 h
Yield: 25 %

Procedure:
A suspension of 20 g (0.082 mole) of 6-(3-thenoylamino)-purine in 1 l of absolute tetrahydrofuran is added dropwise to a stirred suspension of 6.5 g (0.17 mole) of lithium aluminum hydride in 350 ml of absolute tetrahydrofuran at 80° C. After 3 hours, the excess hydride is decomposed with sodium sulfate decahydrate, the residue is filtered off, the filtrate is brought to dryness and the resulting oily crystal slurry is crystallized several times from tetrahydrofuran. 6-(3-Thienylmethylamino)-purine is obtained in a yield of 25%.
Reaction SMILES: S(C)C.[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:36])[C:14]([C:34]#[N:35])=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7].[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH3:4][O:5][C:6]([C@H:8]1[N:12]2[C:13](=[O:36])[C:14]([CH2:34][NH2:35])=[C:15]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]2[S:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(CN)c(=O)n21
Temperature: 100 °C
Yield: 71.7 %

Procedure:
BH3.Me2S (250 μL, 2M in THF, 0.5 mmol) was added dropwise to a solution of 6a (50 mg, 0.11 mmol) in dry THF (4 mL) at rt. The reaction vessel was sealed and heated for 60 s at 100° C. using microwave irradiation. The reaction mixture was cooled to room temperature, diluted with CH2Cl2, poured onto ice-cold aqueous HCl (1M) and agitated. The pH was then adjusted to ˜10 with 2M aqueous NaOH and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried and concentrated. The crude product was dissolved in MeOH and swirled with Amberlyst 15. The solid phase was transferred to a filtration funnel and washed with MeOH. The product was released by addition of 10% NH3 in MeOH and eluted with MeOH. Concentration of the filtrate gave 7a as a yellow solid (36 mg, 72%): [α]D−44 (c 0.25, CHCl3); IR λ 2958, 2854, 1747, 1631, 1492, 1440, 1259, 1214 cm−1; 1H NMR (400 MHz, CDCl3) δ7.83 (d, J=8.2, 1H), 7.78 (d, J=8.1, 1H), 7.71 (d, J=8.7, 1H), 7.54-7.00 (m, 9H), 5.74 (dd, J=8.6, 2.7, 1H), 4.25-4.11 (m, 2H), 3.96-3.51 (m, 8H), 3.48 (dd, J=11.8, 2.7, 1H); 13C NMR (100 MHz, CDCl3) δ168.1, 161.3, 153.5, 148.9, 135.8, 133.8, 133.6, 131.2, 129.7, 129.3, 128.7 (splitted), 128.5 (splitted), 127.3, 126.3, 125.9, 125.5, 124.4, 123.2, 118.4, 116.6, 64.2, 53.6, 38.0, 33.2, 31.7; HRMS (FAB+) calcd for C27H24N2NaO3S 479.1405, obsd 479.1405.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(2-methanesulfonyl-ethyl)-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C35H45N6O4SCl2 [(M+H)+] 715.2595, observed 715.259.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O[CH:18]1C=CC2C(=CC=CC=2)[N:19]1C(OCC)=O)C.C(N(CC)CC)C.[Cl-].C[NH3+]>C(#N)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12](=[O:14])[NH:19][CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)O)c2ccccc2n1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: C[NH3+]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)c1nc(N)nc2ccccc12
Reaction time: 16 h

Procedure:
1.2 100 mg of 2-amino-4-carboxyquinazoline and 261.6 mg of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate are suspended in 5 ml of acetonitrile, and 146.6 μl of triethylamine are added. 53.6 mg of methylammonium chloride are added, and the mixture is stirred at 80° (bath temperature) for 16 hours. The mixture is cooled, the solvent is removed, and the product is purified by means of RP flash chromatography (Isco Compamion®);
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([NH:9][CH3:10])=[O:8])[CH2:3][CH2:2]1>CO.[Pd]>[NH2:15][C:14]1[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1NC1CC1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cccc(N)c1NC1CC1
Reaction time: 3 h

Procedure:
To a solution of 2-(cyclopropylamino)-N-methyl-3-nitrobenzamide (1.76 g, 7.48 mmol) in MeOH (25 mL) was added palladium 10 wt % on carbon (180 mg, 75 mmol) under N2. After flushing the flask with N2 for 2 min, the solution was stirred under a H2 balloon for 3 h. LC-MS showed the reaction was complete. The reaction mixture was filtered and the filtrates collected, rinsed with MeOH and concentrated. The residue was purified by column chromatography on a silica gel column using EtOAc:DCM (1:1) as eluent to give 3-amino-2-(cyclopropylamino)-N-methylbenzamide: 1H NMR (400 MHz, CDCl3) δ 6.85-6.80 (m, 3H), 6.20 (br, 1H), 5.94 (br, 1H), 4.07 (br, 1H), 2.98 (d, J=4 Hz, 3H), 2.63-2.55 (m, 1H), 0.65-0.53 (m, 4H); LCMS (ESI) m/z 206.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:21]=1.C(N(CC)C(C)C)(C)C.CC1CCCO1.CCCP(=O)=O>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:21]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2ncccc2F)c(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Solvent: CC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a refluxing mixture of 2,4-dichloro-5-(3-fluoropyridin-2-yl)benzoic acid (Preparation 27A, 159 g, 0.554 mol), ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (154 g, 0.665 mol), N,N-diisopropylethylamine (215 g, 1.66 mol) and 2-methyltetrahydrofuran (4.8 L), was added propylphosphonic anhydride solution (989 mL, 1.66 mol, >50% by weight in EtOAc) and the reaction maintained at reflux for 6 hours. After cooling to room temperature, the reaction was diluted with water (6 L) and extracted with 2-methyltetrahydrofuran (2×1.5 L). The combined organic layers were concentrated in vacuo to provide a slurry which was filtered and the solid washed with ethyl acetate (3×200 mL) to give the title compound as a white solid (215 g, 79%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:21])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:21])[CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
200 mg of 2-acetylamino-6-chloro-4-phenylquinoline were introduced in portions into 4 ml of 100% strength HNO3 at 0° C. and stirred at 0° C. to 5° C. for 30 min, and the reaction mixture was poured into ice-water. Neutralization with 2N NaOH was followed by extraction with ethyl acetate and removal of the solvent by distillation. The solid residue was boiled several times with diisopropyl ether, and the solvent of the filtrate was evaporated until the substance separated out as crystals.
Reaction SMILES: [Na+].[F:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][S:11]([O-])(=[O:13])=[O:12])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>CN(C)C=O.C(OCC)C>[F:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][S:11]([Cl:19])(=[O:13])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])CCCOc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=S(=O)(Cl)CCCOc1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-fluorophenol (5.0 g, 44.6 mmol) in 50 mL of toluene was added sodium hydride (60% dispersion in mineral oil, 1.78 g, 44.6 mmol) at ambient temperature (22° C.). After 20 minutes, a solution of 1,3-propane sulfone (3.9 mL, 44.6 mmol) in toluene was added slowly and the mixture was stirred for 16 hours. The reaction was quenched by the addition of methanol and the mixture was concentrated in vacuo to an off-white solid. This solid was suspended in ethyl acetate, filtered, and the solids were collected and dried to give 10.9 g of 3-(4-fluorophenoxy)-propane-1-sulfonic acid sodium salt as an off-white powder. A stirred solution of 3-(4-fluorophenoxy)-propane-1-sulfonic acid sodium salt (2.0 g, 7.8 mmol) in 10 mL of thionyl chloride and one drops of dimethylformamide was heated at reflux for 16 hours. The mixture was then cooled to 0° C., diluted with 25 mL of diethyl ether, and the reaction was quenched by the slow addition of water. The organic layer was removed and the aqueous layer was extracted with 25 mL of diethyl ether. The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration gave 1.75 g of 3-(4-fluoro-phenoxy)-propane-1-sulfonyl chloride as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 6.96-7.00 (m, 2 H), 6.80-6.84 (m, 2 H), 4.10 (t, 2 H, J=5.5 Hz), 3.91 (t, 2 H, J=7.5 Hz) 2.47-2.54 (m, 2 H).
Reaction SMILES: [C@@H:1]12[O:7][C@@H:4]([CH:5]=[CH:6]1)[CH2:3][C@H:2]2[C:8]([O:10][CH2:11][CH3:12])=[O:9]>[Pd].C(O)C>[C@@H:1]12[O:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)[C@@H]1C[C@@H]2C=C[C@H]1O2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@@H]2CC[C@H]1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A flask was charged with (1R,2R,4R)-ethyl 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylate (3.91 g, 23.25 mmol) and ethanol (35 mL). The solution was degassed with nitrogen for 5 minutes, then palladium on carbon (5 wt. % wet) (1.0 g, 0.470 mmol) was added portionwise. The flask was evacuated and backfilled three times with nitrogen, then evacuated and backfilled with hydrogen (balloon). The reaction was stirred overnight at room temperature. The reaction was filtered through a plug of Celite and washed several times with ethanol, making sure to keep the catalyst wet with solvent (a layer of sand was added after the first wash). The filtrate was concentrated to afford (1R,2R,4S)-ethyl 7-oxabicyclo[2.2.1]heptane-2-carboxylate (3.63 g, 21.33 mmol, 92% yield). 1H NMR (400 MHz, CHLOROFORM-d) S=4.82 (d, J=5.0 Hz, 1H), 4.72 (t, J=5.0 Hz, 1H), 4.66 (t, J=5.0 Hz, 1H), 4.63-4.59 (m, 1H), 4.22-4.10 (m, 3H), 3.08-2.97 (m, 1H), 2.59 (dd, J=4.9, 9.1 Hz, 1H), 2.14 (dtd, J=2.6, 5.0, 12.3 Hz, 1H), 1.95-1.87 (m, 1H), 1.83-1.63 (m, 4H), 1.62-1.41 (m, 3H), 1.34-1.21 (m, 4H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methylcyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (229 mg, 0.50 mmol) in dry MeOH (5 mL) was added 10% palladium on charcoal (53 mg), nitrogen was bubbled through solution for 10 min, then it was displaced by hydrogen, and the mixture was stirred at room temperature for 24 h. The mixture was filtered through celite washing with MeOH, and filtrate was concentrated under reduced pressure to give 199 mg of crude 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methylcyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester, which was used in the following step without purification.
Reaction SMILES: [O:1]=[C:2]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9](C2C=CC(OCC)=CC2=C=O)[CH2:8][CH2:7]1.[OH-:34].[Na+].[ClH:36]>CO>[ClH:36].[O:1]=[C:2]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:30]2[CH:25]=[CH:24][C:23]([C:2]([OH:1])=[O:34])=[CH:32][CH:31]=2)[CH2:10][CH2:11]1
Reactant: CCOC1=CC(=C=O)C(N2CCN(CCCC(=O)c3ccc4c(c3)CCC(=O)N4)CC2)C=C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccc(C(=O)O)cc4)CC3)ccc2N1

Procedure:
2.0 Grams of 6-{1-oxo-4-[4-(4-ethoxy-carbonylphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril and 0.6 g of sodium hydroxide were mixed in 70 ml of methanol and refluxed by heating for 2 hours. To the reaction mixture was added 5 ml of concentrated hydrochloric acid and the mixture was concentrated under a reduced pressure to dryness. The residue was recrystallized from ethanol-water to obtain 0.6 g of 6-{1-oxo-4-[4-(4-carboxyphenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril monohydrochloride in colorless needle-like crystals.