Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17]>>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Product: CCC(=O)NC1CCc2c(-c3ccc(C#N)cc3)cncc21
Yield: 79 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 4-cyanophenylboronic acid to give the title compound as light green powder in 79% yield. MS: 292.1 (M+H+).
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[C:4]1=[O:15])=O.Cl.[NH2:17]O>CO>[CH3:14][O:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][C:3]1[CH:1]=[N:17][O:15][C:4]=12
Reactant: COc1cccc2c1CCC(C=O)C2=O
Reactant: NO
Agent: Cl
Solvent: CO
Product: COc1cccc2c1CCc1cnoc1-2

Procedure:
A mixture of the product obtained in step (i) (23.8 g, 0.11 mol) and hydroxylamine hydrochloride (8.2 g, 0.12 mol) in methanol (300 ml) is refluxed for ten minutes and then evaporated off under vacuum. Water is added thereto and the mixture is extracted with ethyl ether affording 19 g of the compound indicated in the title; m.p. 84°-86° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7 %

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (800 mg) was dissolved in dichloroethane (16 ml), added with 1,2,3,4-tetrahydroquinoline (0.50 ml), sodium triacetoxyborohydride (1.7 g) and acetic acid (2.3 ml) and stirred at room temperature for 24 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (20 ml) and extracted twice with ethyl acetate (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=10:1) to obtain 90.6 mg of the title compound. Yield: 7%.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[CH2:22]([O:21][CH:20]([O:24][CH2:25][CH3:26])[C:18]1[CH2:17][N:13]2[CH:14]=[CH:15][C:16]3[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=3)=[C:12]2[N:19]=1)[CH3:23]
Reactant: CCOC(=O)C(=Cc1cccn2cc(C(OCC)OCC)nc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(C(OCC)OCC)=N3

Procedure:
From 6h (yield: 97%); mp 242-244° C.; IR (KBr) 3422, 1719, 1252, 1190 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.26 (t, 6H, J=7 Hz), 1.37 (t, 3H, J=7 Hz), 3.71 (m, 4H), 4.38 (q, 2H, J=7 Hz), 6.96 (d, 1H, J=7 Hz), 7.58 (s, 1H), 7.65 (s, 1H), 7.84 (d, 1H, J=7 Hz), 10.40 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 15.3, 61.1, 61.8, 98.8, 101.8, 108.3, 111.0, 114.5, 123.5, 126.4, 132.8, 141.5, 142.6, 161.6; MS m/z 331 (M+, 1), 257 (61), 211 (78), 183 (33), 99 (38), 85 (65), 71 (81), 57 (100). Anal. Calcd for C17H21N3O4: C, 61.62; H, 6.39; N, 12.68. Found: C, 61.27; H, 6.31; N, 12.79.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]1[CH2:37][C@@:35]2([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]2[OH:38])[C@@:30]2([CH:39]=[CH2:40])[C@H:21]1[C:22]1[CH:23]=[CH:24][C:25]([OH:41])=[CH:26][C:27]=1[CH2:28][CH2:29]2>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@@:30]3([CH:39]=[CH2:40])[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:41])=[CH:26][C:27]=2[CH2:28][CH2:29]3)[CH2:2][CH2:3]1
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCN1CCOCC1)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with morpholine (10 equivalents) with the addition of sodium carbonate analogously to instructions 17.2, 32 mg of mixture 30b yields 32 mg of amine 35b as a colorless foam (GC-MS: m/z theor.: 467, pract.: 467).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:19]=1Cl.O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:19]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
To a solution of 2-mercapto-5-trifluoromethyl-benzothiazole (239) (470 mg, 2.0 mmol) in DMF (20 mL) was added NaH (Aldrich, 60% suspension in hexanes, 80 mg, 2.0 mmol). After the resulting mixture was stirred at ambient temperature for 20 minutes, was added 1,2,3-trichloro-5-nitrobenzene (Acros, 452 mg, 2.0 mmol). The mixture was then heated at 60° C. for 4 hours. After cooled to room temperature, the mixture was poured to water and stirred for 1 hour. The solid product was collected by vacuum filtration to give 258 as a pale yellow solid (840 mg, 99%) which was used in the next reaction without further purification.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][NH:18][CH3:19])=[CH:15][CH:16]=1)SC)#[N:2].[CH2:20]([NH2:23])[C:21]#[CH:22]>CO>[C:1]([NH:3][C:4]([NH:23][CH2:20][C:21]#[CH:22])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][NH:18][CH3:19])=[CH:15][CH:16]=1)#[N:2]
Reactant: CNCc1ccc(CSCCN=C(NC#N)SC)o1
Reactant: C#CCN
Solvent: CO
Product: C#CCNC(=NCCSCc1ccc(CNC)o1)NC#N

Procedure:
A mixture of N-cyano-N'-{2-[(5-methylaminomethyl-2-furyl)methylthio]ethyl}-S-methylisothiourea [prepared according to the procedure described in Belgian Pat. No. 857,388] and propargylamine in methanol is stirred and heated under a positive pressure of nitrogen to give, after workup and chromatography, the title compound.
Reaction SMILES: Br[CH2:2][C@@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].FC(F)(F)S(O[C:17]1[C:22]([F:23])=[CH:21][C:20]([CH:24]2[CH2:29][CH2:28][Si:27]([CH2:36][CH2:37][CH3:38])(C3C=CC=CC=3)[CH2:26][CH2:25]2)=[CH:19][C:18]=1[F:39])(=O)=O>>[CH2:36]([Si@H:27]1[CH2:26][CH2:25][C@H:24]([C:20]2[CH:19]=[C:18]([F:39])[C:17]([CH2:2][C@@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:22]([F:23])[CH:21]=2)[CH2:29][CH2:28]1)[CH2:37][CH3:38]
Reactant: CCC[Si]1(c2ccccc2)CCC(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Reactant: CCCCCC[C@H](F)CBr
Product: CCCCCC[C@H](F)Cc1c(F)cc([C@H]2CC[Si@H](CCC)CC2)cc1F

Procedure:
The general procedure of Example 18 was repeated using (S)-1-bromo-2-fluorooctane and (2,6-difluoro-4-(4-n-propyl-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.
Reaction SMILES: [Na].[CH3:2][OH:3].C[O-].[Na+].O.[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:2][O:3][CH2:14][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccccc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: COC[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C

Procedure:
Slices of metal sodium (17.4 g, 0.755 mol) were added in small portions to methyl alcohol (250 ml) agitated at room temperature, to prepare sodium methoxide. After metal sodium pieces disappeared, a solution obtained by dissolving compound (C) (200.0 g, 0.581 mol) previously obtained, in dry toluene (600 ml) was gradually added through a dropping funnel so that the inner temperature was kept in the range of 50°~60° C. After the dropwise addition, the mixture was refluxed for 4 hours and then cooled, followed by adding water (20 ml), transfering the mixture into a separating funnel, washing separated toluene layer with water till the aqueous layer became neutral, distilling off toluene under reduced pressure, distilling the residuce under reduced pressure, and collecting a fraction having a boiling point of 105°~108° C./1.5 mmHg to obtain trans-4-methyloxymethyl-1-phenylcyclohexane (D) (100.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([S:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([S:21]([CH2:22][CH2:23][OH:24])=[O:36])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(SCCO)cc2c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(S(=O)CCO)cc2c1O

Procedure:
This compound was prepared from N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(2-hydroxyethyl)sulfanyl]-3-quinolinecarboxamide (Example No. 171) and an equimolar amount of m-chloroperbenzoic acid according to a procedure similar to described in Example 175.
Reaction SMILES: [CH3:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[N:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[N:11]=1)[C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:7][CH:8]=1
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(N(C)c2ccc(NS(C)(=O)=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a suspension of N-methyl-N-(2-methylquinazolin-4-yl)benzene-1,4-diamine 0.132 g (0.5 mmol) with Et3N 0.2 mL in CH2Cl2 10 mL was added methylsulfonyl chloride 0.115 g (1.0 mmol) at 23° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 30 mL, washed with water, sat. Na2CO3 aqueous solution and dried on anhydrous MgSO4. After removal of solvents, the crude product was subjected to gradient column chromatography (EtOAc/hexanes, 0% to 100%), but the compound was only obtained in <80% purity. Therefore, the crude compound was purified with preparative HPLC to give the titled compound in 15% yield. 1H NMR (CD3OD, 400 MHz): δ 7.86-7.82 (m, 1H), 7.72-7.67 (m, 1H), 7.44-7.42 (m, 4H), 7.29-7.24 (m, 1H), 6.94 (d, 1H, J=8.6 Hz), 3.84 (s, 3H), 3.07 (s, 3H), 2.78 (s, 3H). m/e: 343.1339 (M+1).
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]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.Br[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1>>[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[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]([CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:19]=1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: Clc1ccc(OCCBr)cc1
Product: Cc1c(-c2nn(CCOc3ccc(Cl)cc3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 16, step c) and 1-(2-bromo-ethoxy)-4-chloro-benzene using the procedure described in example 14. MS: ESI (negative): 520, 522 (M−H).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:45])[C@@H:16]2[CH2:23][N:22]3[C:24]4[CH:25]=[C:26]([C:37](OC)=[O:38])[CH:27]=[CH:28][C:29]=4[C:30]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:21]3[C:20]3[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=3[O:18][CH2:17]2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.C(Cl)CCl.[CH3:51][O:52][CH:53]([O:61][CH3:62])[CH2:54][N:55]([CH3:60])[S:56]([NH2:59])(=[O:58])=[O:57]>O1CCOCC1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:31]1([C:30]2[C:29]3[CH:28]=[CH:27][C:26]([C:37]([NH:59][S:56]([N:55]([CH2:54][CH:53]([O:52][CH3:51])[O:61][CH3:62])[CH3:60])(=[O:58])=[O:57])=[O:38])=[CH:25][C:24]=3[N:22]3[C:21]=2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17][C@H:16]([N:15]([CH3:45])[C@H:12]2[CH2:13][CH2:14][N:10]([C:8]([O:7][C:3]([CH3:4])([CH3:6])[CH3:5])=[O:9])[CH2:11]2)[CH2:23]3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)[C@H]1CCN(C(=O)OC(C)(C)C)C1)COc1ccccc1-3
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)[C@H]1CCN(C(=O)OC(C)(C)C)C1)COc1ccccc1-3)OC
Temperature: 75 °C
Reaction time: 12 h

Procedure:
1M KOH (3.5 eq) was added to a 0.3M solution of methyl (7R)-7-[[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (1 eq) in dioxane and the mixture was stirred at 75° C. for 12 h. The pH was adjusted at 0° C. by addition of 1N HCl (until pH=6), then all volatiles were evaporated, the solid residue was taken in CHCl3 and salt was filtered off. The filtrate was concentrated in vacuo to afford a residue that was taken in dry DCM (0.05M); DMAP (3.5 eq), EDC (1.5 eq) and N-(2,2-dimethoxyethyl)-N-methylsulfamide (1.5 eq; prepared as described in Example 1, step 1) were added and the mixture was stirred at 40° C. for 1 h. The residue obtained after evaporation was extracted with EtOAc. The combined organic phases were washed with 1M HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4 and concentrated to afford the title compound which was used without further purification. (ES+) m/z 754 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Br)cnc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 140 °C
Yield: 24.3 %

Procedure:
A mixture of 5-bromo-2-chloronicotinic acid (2.36 g, 10 mmol), 4-trifluoromethoxyphenol (2.14 g, 12 mmol) and K2CO3 (4.14 g, 30 mmol) in DMF (30 mL) was heated at 140° C. for 24 h. After cooling to room temperature the mixture was diluted with water (150 mL) and the pH was adjusted to 6 with acetic acid. The mixture was extracted with EtOAc (3×50 mL) and the combined organic extracts were dried (MgSO4) and evaporated to give an oil. This was triturated with water to give a sticky solid which was filtered and washed with water and then pentane. The resulting beige solid was suspended in further pentane, sonicated, filtered and dried in vacuo at 60° C. to give the product (0.92 g, 24%) as a beige solid; (δH (CDCl3, 300 MHz) 7.19 (2H, m), 7.28 (2H, m), 8.35 (1H, s), 8.58 (1H, s); MS m/z (TS+) 378, 380 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:36])[C:19]1[C:24](Br)=[CH:23][C:22]([F:26])=[C:21]([F:27])[C:20]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[CH3:16][O:17][C:18](=[O:36])[C:19]1[C:24]([NH:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[CH:23][C:22]([F:26])=[C:21]([F:27])[C:20]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1c(NNC(=O)OC(C)(C)C)cc(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pd2(dba)3 (4 mol %), t-butylcarbazate (4.00 equivalents), dppf (12 mol %) and Cs2CO3 (1.00 equivalent) are added to a solution of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (1.00 equivalent) in PhMe. The reaction mixture is heated in a sealed vial charged under a N2 atmosphere to 100° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture is diluted with methylene chloride and filtered. The filtrate is concentrated under reduced pressure. The product is purified by trituration or flash column chromatography if further purification is necessary.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH3:5][O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])=[CH:9][CH:8]=1.[Cl-].[NH4+]>C1COCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:22][CH:21]=2)([OH:12])[CH2:1][CH3:2])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Into a reactor were introduced 31.9 mL (30.9 mol; 0.97 M THF solution) of ethylmagnesium chloride and 20 mL of THF under a nitrogen atmosphere. The contents were cooled to 4° C. Thereafter, a solution prepared by mixing 5.00 g (20.6 mmol) of 4,4′-dimethoxybenzophenone with 20 mL of THF was gradually added dropwise thereto, and this mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 3.06 g (55%) of the target compound as a light-yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:18]=1)[N:10]([CH3:26])[N:9]=[CH:8]2>[Pd].C1COCC1>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:13]=2[C:14]2[CH:15]=[N:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH:18]=2)[N:10]([CH3:26])[N:9]=[CH:8]3)=[C:2]([F:1])[CH:30]=1
Reactant: Cn1ncc2cc(Oc3ccc([N+](=O)[O-])cc3F)c(-c3cnn(C(=O)OC(C)(C)C)c3)cc21
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1ncc2cc(Oc3ccc(N)cc3F)c(-c3cnn(C(=O)OC(C)(C)C)c3)cc21
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a 3 gallon tank is added tert-butyl 4-(5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (433.0 g, 952.8 mmol) followed by THF (6.5 L) and Pd/C (21.65 g, 10% Pd/C and 21.65 g, 5% Pd/C). The mixture is heated to 35° C. under hydrogen gas for 2 hours. The reaction is then cooled to RT and allowed to stir under hydrogen gas overnight, then is heated to 40° C. under hydrogen gas for seven hours. An additional 2 g Pd/C (1 g, 10% Pd/C and 1 g, 5% Pd/C) is added and stirred under hydrogen gas for another hour and cooled to RT. The mixture is again stirred under hydrogen gas overnight and the reaction is completed. The mixture is filtered over a combination of GFF® and Watman® paper. The filtrate is concentrated to a slightly yellow solid (446 g, 110% recovery).
Reaction SMILES: C(OC([N:8]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:44])[N:14]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:35])[N:20]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(ON(C(=O)CCCCNOCC1C=CC=CC=1)CCCCC#N)C1C=CC=CC=1>C(Cl)Cl>[CH2:28]([O:27][N:20]([C:19](=[O:35])[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:13](=[O:44])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Yield: 57.1 %

Procedure:
Compound (7) (2.85 g, 3.99 mmol) in CH2Cl2 was treated with excess TFA following the procedure used for (5). Silica gel column chromatography, eluting with 3:2 EtOAc/hexane gave 1.4 g (57%) of (8) as an oil: NMR δ 1.43-1.83 (m, 12 H), 2.20-2.50 (m, 6 H), 2.90 (t, 2 H, J=6), 3.60 (t, 4 H, J=6), 4.63 (s, 2 H), 4.75 (s, 4 H), 7.28 (s, 5 H) , 7.33 (s, 10 H). Anal. (C36H46N4O5) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CC(C)S(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)S(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
2 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 2-chloro-4-(isopropylthio)benzonitrile. 1.6 g of 2-chloro-4-(isopropythio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(isopropylthio)benzoic acid. 1 g of 2-chloro-4-(isopropylthio)benzoic acid was reacted via Procedure R to give 2-chloro-4-(isopropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(isopropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide. MS (Q1) 449.1 (M)+.