Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][C:21]=2[F:30])=[C:14]([CH3:31])[N:13]=1>C1COCC1.CCOC(C)=O>[NH2:11][C:12]1[N:17]=[C:16]([Cl:18])[C:15]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([CH2:24][OH:25])=[CH:22][C:21]=2[F:30])=[C:14]([CH3:31])[N:13]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(Cl)c1Cc1ccc(CO)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminium hydride (1M in hexanes, 8.8 mL) was added dropwise over 10 min to a suspension of the product from example 22 step (iii) (0.78 g) in THF (10 mL) at 0° C. The mixture was allowed to warm to rt and stirred for 1 h. EtOAc (10 mL) was added and then the mixture stirred for 10 min before being added to ice/water (100 mL). The mixture was stirred for 30 min and then diluted with EtOAc (50 mL). The organic phase was separated and the aqueous was extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to afford the subtitle compound, 0.3 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:20])=[CH:15][N:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)O)s1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)N2CCOCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
To a solution of (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetic acid (Example 3) (0.09 g, 0.25 mmol) in CH2Cl2 (5.0 mL) and DMF (0.5 mL) were added EDCI (0.05 g, 0.27 mmol), DMAP (0.02 g, 0.12 mmol), triethylamine (0.1 mL, 0.75 mmol) and morpholine (0.03 mL, 0.30 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then washed with 1 M HCl (2×15 mL) and the organic layer was collected. The organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification using preparative HPLC afforded the desired product (0.01 g) in 10% yield.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[C:10](=[O:13])[CH2:11][O:12][C:8]=2[C:7]=1[CH2:16][CH:17]([C:21](=O)[CH3:22])[C:18](=O)[CH3:19].C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[CH3:22][C:21]1[C:17]([CH2:16][C:7]2[C:8]3[O:12][CH2:11][C:10](=[O:13])[C:9]=3[CH:14]=[CH:15][C:6]=2[O:5][CH3:4])=[C:18]([CH3:19])[NH:3][N:2]=1
Reactant: NN
Reactant: COc1ccc2c(c1CC(C(C)=O)C(C)=O)OCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1Cc1c(C)n[nH]c1C)OCC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
A solution of hydrazine monohydrate (0.0102 g, 0.203 mmol) in water (1.25 mL) was cooled to 0° C., and added with a solution of 3-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]pentane-2,4-dione (0.0533 g, 0.193 mmol) in acetic acid (2 mL), and the mixture was stirred for 18 hours with warming it to room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, thereby made basic, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 7-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-6-methoxybenzofuran-3(2H)-one (0.0427 g, 81%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44])[CH2:38][NH2:39].C(N(CC)C(C)C)(C)C.CS(C)=O>O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[C:27]([NH:39][CH2:38][C:37]6[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:35]([O:34][CH3:33])[CH:36]=6)[N:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccnc(Cl)n4)ccc32)n1)c1ccccc1
Reactant: COc1cc(CN)cc(OC)c1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CNc2nccc(-c3ccc4c(c3)ncn4-c3ccnc(N[C@@H](C)c4ccccc4)n3)n2)cc(OC)c1OC
Temperature: 100 °C

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-(2-chloropyrimidin-4-yl)benzimidazol-1-yl]pyrimidine (EXAMPLE 424) (80 mg), 3,4,5-trimethoxybenzylamine hydrochloride (219 mg), and N,N-diisopropylethylamine (0.16 mL) were dissolved DMSO (4 mL) and the resulting solution was heated to 100° C. for 15 hours. Upon cooling the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×25). The combined organic extracts were dried (MgSO4) and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1cc(Cl)ncc1Cl
Product: Fc1ccc(COc2cc(Cl)ncc2Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 12a, using 2,5-dichloro-4-pyridinol (CAN 847664-65-7) and 1-(bromomethyl)-4-fluoro-benzene (CAN 459-46-1) as starting materials and isolated (1.03 g, 62%) as white solid; LC-MS (UV peak area, m/z) 98.6%, 272.0040 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN2CCCC2)cc1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (4.56 g, 30 mmol) in dry DMF (60 mL) was added cesium carbonate (31.3 g, 96 mmol, 3.2 eq.) and 1-(2-chloroethyl)pyrrolidine hydrochloride (8.1 g, 48 mmol, 1.6 eq.). The reaction was heated at 80° C. for 20 h. The reaction mixture was cooled to ambient temperature then water (240 mL) was added. The mixture was partitioned with ethyl acetate (250 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined extracts were washed with water (240 mL), brine (50 mL), dried (Na2SO4), filtered then concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (90:5:5 hexane:THF:TEA) to give the desired product as an oil (5.3 g, 71%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1.[C]=S.[Br:20]Br.[OH-].[Na+]>O>[Br:20][C:5]1[CH:4]=[CH:3][C:2]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:1][CH:6]=1
Reactant: CCOC(=O)N1CCN(c2ccccn2)CC1
Reactant: BrBr
Agent: [C]=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reaction time: 18 h

Procedure:
To a stirred and cooled (<10° C.) mixture of 150 g of ethyl 4-(2-pyridinyl)-1-piperazinecarboxylate and 1535 ml of carbon sulfide were added dropwise 32.8 ml of bromine. Upon completion, stirring was continued for 18 hours, while meantime the mixture was allowed to reach room temperature. At a temperature below 20° C., there was added a solution of 70 g of sodium hydroxide solution 10N in 300 ml of water. After stirring for 3 hours at room temperature, the layers were separated. The aqueous phase was extracted twice with trichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. 46 ml of benzene were added to the residue and the whole was evaporated again. Upon standing for 48 hours, the product was solidified. The oily phase was decanted and the solid product was crystallized twice from 2,2'-oxybispropane at 10° C. It was filtered off and dried, yielding 100 g of ethyl 4-(5-bromo-2-pyridinyl)-1-piperazinecarboxylate; mp. 68° C. (interm. 11).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH2:28][CH2:27]1.CS(N)(=O)=O.[N:55]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1>>[N:55]1([S:59]([NH:62][C:34](=[O:36])[C:33]2[CH:37]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]=2[F:38])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)CCC(F)(F)CC1

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.17 g, 56%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.72-8.59 (m, 1H), 7.69-7.61 (m, 1H), 6.64-6.52 (m, 1H), 4.31-4.19 (m, 4H), 3.76 (s, 2H), 2.35-2.20 (m, 2H), 2.08-1.73 (m, 7H), 1.69-1.58 (m, 2H), 1.17 (s, 3H), 0.99-0.89 (m, 2H), 0.71-0.61 (m, 2H); MS (ES+) m/z 461.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:28][C:27]1[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Reactant: Nc1ccc(F)cc1
Product: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1c(F)cc(F)c(F)c1C

Procedure:
Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (1.0 g) and p-fluoroaniline (0.39 g), the procedure of Reference Example 8 is repeated to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(4-fluorophenyl)aminoacrylate, which is then treated with 60% sodium hydride (0.15 g) as in Reference Example 9 to give ethyl 1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.64 g), as white crystals (recrystallized from ethanol), m.p. 256°-259° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.Cl.[OH:44][CH:45]1[CH2:48][NH:47][CH2:46]1.CN(C=O)C>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([OH:26])([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)[C:27]3[CH:28]=[N:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[CH:8]=2)[N:3]=[C:2]([N:47]2[CH2:48][CH:45]([OH:44])[CH2:46]2)[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: OC1CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CC(O)C3)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (100 mg, 0.164 mmol, Intermediate 65), 3-hydroxyazetidine hydrochloride (189 mg, 1.64 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The reaction solution was taken up into EtOAc, transferred to a reparatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H27ClF3N7O2, 645.2. m/z found, 646.3 [M+H]+. 1H NMR (600 MHz, CD3OD) δ ppm 8.78 (d, J=2.0 Hz, 1H), 8.13 (dd, J=2.5, 0.4 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.01 (dd, J=8.2, 2.0 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J=1.4 Hz, 1H), 7.64-7.59 (m, 2H), 7.57 (dd, J=8.8, 2.2 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.50-6.46 (m, 1H), 6.35 (s, 1H), 4.55-4.49 (m, 1H), 4.39-4.34 (m, 2H), 4.34 (s, 2H), 3.99-3.93 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N+:12]([O-])=[C:11]([CH3:17])[CH:10]=[CH:9]2)(=[O:4])=[O:3].C1(C)C=CC(S([Cl:27])(=O)=O)=CC=1>ClCCCl>[Cl:27][CH2:17][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=2)[N:12]=1
Reactant: Cc1ccc2cc(NS(C)(=O)=O)ccc2[n+]1[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccc2nc(CCl)ccc2c1
Reaction time: 17 h

Procedure:
6-Methanesulphonamido-2-methylquinoline-1-oxide (1.65 g) and p-toluenesulphonyl chloride (1.72 g) were heated under reflux for 1 hour in 1,2-dichloroethane solution, and the reaction mixture was then stood at room temperature for 17 hours. The reaction mixture was then washed twice with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated to give a gum which solidified when triturated with ether. Recrystallisation from toluene gave the title compound, yield 0.75 g, m.p. 160°-162°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=O.C=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CCCC)CCCC)CCC>C(=O)(OCC)OCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=Cc1ccccc1
Reactant: COc1ccccc1C(=O)Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(=O)OCC
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccccc1C=Cc1ccccc1
Yield: 49 %

Procedure:
The procedure described in Example 1 is followed, except that 17.1 g (0.1 mol) of 2-methoxybenzoyl chloride, 13 g (0.125 mol) of styrene, 23.2 g (0.125 mol) of tri-n-butylamine and 0.225 g (0.001 mol) of palladium acetate are used. After a reaction time of 3 hours at a bath temperature of 140° C., in 100 ml of diethyl carbonate as the solvent, 10.3 g (0.049 mol) of 2-methoxystilbene, corresponding to a yield of 49% of theory, are obtained; melting point 69°-70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N+:17]([O-])=O.[H][H]>CO.[Ni]>[NH2:17][C:3]1[CH:4]=[CH:5][C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2ccccc2)cc1N

Procedure:
1.9 g. of 2-amino-1-nitro-4-phenylsulfonylbenzene is treated in methanol with hydrogen at 4 atmospheres in the presence of Raney nickel catalyst for 2 hours. The catalyst if filtered off and the filtrate stripped under vacuum. Recrystallization of the residue gives 1,2-diamino-4-phenylsulfonylbenzene.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([OH:36])[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([OH:36])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCCNCC1
Yield: 128.4 %

Procedure:
tert-Butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate (0.0039 g, 0.0080 mmol) was treated with a mixture of trifluoroacetic acid and DCM (1:1) for 1 hour. The reaction was concentrated to provide 4 mgs of the desired material as a solid. MS ESI (+) m/z 390 (M+1) detected.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH2:7]1)=O)C.C(OC(N1CCC(N)CC1)=O)(C)(C)C.N(C(C)C)=C=O.[BH4-].[Li+]>C1COCC1>[C:36]([N:8]1[CH2:9][CH2:10][C@@H:11]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C@H:6]([CH2:4][OH:3])[CH2:7]1)(=[O:40])[CH2:37][CH2:38][CH3:39]
Reactant: CCCC(=O)N1CC[C@@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](C(=O)OCC)C1
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)N=C=O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCCC(=O)N1CC[C@@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](CO)C1

Procedure:
(±)-(trans)-1-Butyryl-4-[4-(2-methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-3-carboxylic acid ethyl ester was made following general procedure in Scheme 5, substituting (±)-4-amino-1-benzyl-piperidine-3-carboxylic acid ethyl ester (5) for 4-amino-piperidine-1-carboxylic acid tert-butyl ester and substituting butyl chloride for 2-isocyanato-propane. To the solution of (±)-(trans)-1-butyryl-4-[4-(2-methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-3-carboxylic acid ethyl ester (121 mg, 0.21 mmol) in THF (5 mL), was added lithium borohydride in THF solution (1.07 mL, 2.1 mmol) and the resultant solution was stired at 0° C. for 2 h. The solvent was removed in vacuo and the crude material was purified by HPLC to give the title compound. 1H NMR (300 MHz, MeOD) δ 8.75 (d, 1H), 8.32 (dd, 1H), 8.24 (d, 1H), 7.93 (d, 1H), 7.70 (m, 3H), 7.38 (m, 3H), 4.00 (m, 3H), 3.20 (m, 2H), 2.88 (m, 1H), 2.55 (s, 3H), 2.46 (m, 1H), 2.28 (m, 2H), 1.50 (m, 3H), 1.24 (m, 2H), 0.90 (dd, 3H); LC/MS m/z 525 (M+H)+
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)=O>CN(C)C=O.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: FC(F)(F)CCl
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)CSc1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A two-necked flask having a dry ice condenser fitted on top was charged with 50 ml of dry dimethylformamide and 2 g of a 60% strength by weight suspension of sodium hydride in paraffin, and subsequently 7.3 g of 4-chlorothiophenol in 10 ml of dimethylformamide were added dropwise. Chlorotrifluoroethane was then passed in at a reaction temperature of about 60° C., until the gas began to condense in the dry ice condenser. The mixture was stirred for a further 5 hours and the course of the reaction was monitored by thin-layer chromatography (silica gel; ethyl acetate/petroleum ether 1/5). The reaction mixture was worked up by pouring into water and extracting with dichloromethane. The combined organic extracts were dried and the solvent was distilled off at reduced pressure. The oily residue was subsequently distilled (43°-45° C./0.1 mbar), giving 8.8 g of 4-chloro(2',2',2'-trifluoroethylthio)benzene
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34]>ClCCl>[CH3:36][O:35][C:33]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1)=[O:34]
Reactant: COC(=O)Cl
Reactant: N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reaction time: 3 h
Yield: 67.7 %

Procedure:
(5R)-3-(4-((3R)-3-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (200 mg, 0.5 mM) in dichloromethane (20 ml) was cooled to 0° and treated with 5% sodium bicarbonate solution (5 ml). The resulting suspension was stirred vigorously, methyl chloroformate (245 mg, 2.6 mM) added, and stirring continued for 3 hours at ambient temperature. The organic layer was separated, washed with 2% sodium dihydrogen phosphate (2×10 ml), brine (10 ml), and dried (magnesium sulfate), to give the desired product (143 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.F[C:14]1[N:43]=[CH:42][CH:41]=[CH:40][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[C:31]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[N:33]=3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][CH:20]=1)=[O:17].Cl>C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCOC(C)=O.O.O>[CH3:39][NH:38][C:34]1[N:33]=[C:32]([C:31]2[C:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([NH:18][C:16](=[O:17])[C:15]4[CH:40]=[CH:41][CH:42]=[N:43][C:14]=4[NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:20][CH:21]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:37]=[CH:36][N:35]=1
Reactant: Nc1ccccc1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccnc3F)cc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccnc3Nc3ccccc3)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a brown solution of aniline (0.18 ml, 1.9 mmol) in lithium bis(trimethylsilyl)amide, 11.0m solution in tetrahydrofuran (1.9 ml, 1.9 mmol) was added 2-fluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)nicotinamide (0.200 g, 0.48 mmol). The mixture was sealed and heated to 70° C. After 2 h, the reaction was cooled to ambient temperature. Water was added, and the pH was adjusted with 6N HCl until slightly acidic. Add to EtOAc/water. Wash the mixture 1× with brine. The organic layer was dried over anhyd. sodium sulfate, filtered, and concentrated to give a brown solid. This material was purified by silica gel chromatography using 90/10 dichloromethane/methanol as eluent to give a yellow solid. Further purification was performed by trituration with dichloromethane and methanol to give N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-2-(phenylamino)nicotinamide as a yellow solid. MS m/z=490 [M+1]+. Calc'd for C28H23N7O2: 489.53.