Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:19]CCCO)[CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].C(S(NC)(=O)=O)(C(C(C(F)(F)F)(F)F)(F)F)(F)F.O(C)[Na].BrC[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][OH:57]>COCCOCCOC>[C:1]([S:14]([N:17]([CH2:19][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][OH:57])[CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:11])([F:13])[F:12])([F:8])[F:9])([F:5])[F:6])([F:2])[F:3]
Reactant: OCCCCCCCCCCCBr
Reactant: CN(CCCCO)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CO[Na]
Solvent: COCCOCCOC
Product: CN(CCCCCCCCCCCO)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C

Procedure:
C4F9SO2N(CH3)(CH2)11OH was prepared using a procedure similar to that described above for preparing C4F9SO2N(CH3)(CH2)4OH. 175.9 g C4F9SO2NHCH3 and 121.4 g 25% NaOCH3 were reacted to produce a solution of C4F9SO2NNaCH3 in about 100 mL diglyme. This solution was treated with 141 g 11-bromoundecanol (available from Aldrich) and heated at 100° C. for 20 hr to form a heavy precipitate. The reaction was quenched in about 600 mL warm water and the resulting lower layer was stripped at 50° C./0.5 mTorr to leave 269.9 g of C4F9SO2N(CH3)(CH2)11OH, a low-melting solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](F)(F)F)=[CH:4][CH:3]=1.[Al+3].[Cl-:13].[Cl-:14].[Cl-].[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:23][O:22][C:16]1[CH:21]=[CH:20][C:19]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([Cl:14])[Cl:13])=[CH:18][CH:17]=1
Reactant: [Cl-]
Reactant: COc1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Product: COc1ccc(C(Cl)(Cl)c2ccc(Cl)cc2)cc1

Procedure:
From 4-chlorobenzotrifluoride (180 mg, 1 mmol), AlCl3 (400 mg, 3 mmol) and anisole (108 mg, 1 mmol), red solid (345 mg, 120% crude), contains the benzophenone (ca 30%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][Br:17])=[CH:10][CH:9]=1.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[Br-:17].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][P+:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCCc1ccc(OC2CCCCO2)cc1
Solvent: CN(C)C=O
Product: [Br-]
Product: c1ccc([P+](CCCc2ccc(OC3CCCCO3)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4′-(2-tetrahydropyranyloxy)phenyl)-3-bromopropane 3C (4.2 g) in anhydrous dimethylformamide (11.3 mL) is added triphenylphosphine (6.12 g). The reaction mixture is stirred under nitrogen at 100° C. overnight. The reaction mixture is then cooled to room temperature. The white precipitate is filtered and washed with ethyl acetate, then dried under vacuum.
Reaction SMILES: Br[CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:3].[NH3:13]>CCOCC>[ClH:12].[NH2:13][CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:3]
Reactant: N
Reactant: CC(Br)C#Cc1ccc(Cl)cc1
Solvent: CCOCC
Product: CC(N)C#Cc1ccc(Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product prepared in step (e) above is added, with stirring, to 5 to 10 times excess of ammonia. The mixture is stirred at room temperature for 3 hours. An excess of ether is then added and the precipitate is filtered off. The ether is removed in vacuo and the resulting oil is used directly to prepare the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:22])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]1=[O:23])[CH3:2].[Cl:25]N1C(=O)CCC1=O>ClCCCl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:11]([Cl:25])=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]([F:21])([F:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:7]1=[O:23])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1ccnc(NCC(F)(F)c2ccccn2)c1=O
Solvent: ClCCCl
Product: CCOC(=O)Cn1c(Cl)cnc(NCC(F)(F)c2ccccn2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 6.81 g (20.1 mmol) of [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester and 2.42 g (18.1 mmol) of N-chlorosuccinimide in 100 mL of 1,2-dichloroethane was heated to reflux. An additional 242 mg (1.81 mmol) and 75 mg (0.56 mmol) of NCS were added to the reaction mixture after 1 h and 1.5 h, respectively. After 2.5 h total, the solution was cooled to room temperature and partitioned between dichloromethane (150 mL) and sat. aq. NaHCO3 (200 mL). The layers were separated and the aqueous phase was backwashed with dichloromethane (2×200 mL). The combined organic layers were dried over MgSO4 and the solution concentrated to a volume of 10 mL. This liquid was directly loaded onto a SiO2 column and eluted with 65:35 to 55:45 hexane-EtOAc to give the title compound as a yellow solid: 1H NMR (CDCl3) δ 8.68 (d, 1H, 4.8, Hz), 7.83 (ddd,1H, 7.7, 7.7, 1.6 Hz), 7.9 (dd, 1H, 7.9 Hz), 7.40 (dd, 1H, 4.9, 7.3 Hz), 6.96 (s, 1H), 6.49 (br t, 1H, 5.9 Hz), 4.89 (s, 2H), 4.38 (td, 2H, 13.9, 6.5 Hz), 4.26 (q, 2H, 7.1 Hz), 1.30 (t, 3H, 7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:43][N:44](C)[OH:45].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([N:44]([O:45][CH3:30])[CH3:43])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cccc(COc2nc(C)n(-c3cc(C(=O)O)ccc3C)c(=O)c2Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(COc2nc(C)n(-c3cc(C(=O)N(C)OC)ccc3C)c(=O)c2Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 3-[5-chloro-4-(3-methoxy-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid from step C (230 mg, 0.56 mmol) in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (135 mg, 0.83 mmol). After stirring at ambient temperature for three hours, N,N-dimethylhydroxylamine HCl (80 mg, 0.83 mmol) and triethylamine (0.15 mL, 1.12 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, 5% citric acid and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a light green oil (200 mg, 78%). MS (M+H): 458
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16]C)[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:18][CH3:19])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:20])[CH:5]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:18][CH3:19])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:20])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2

Procedure:
5,6-Dichloro-9a-ethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (15 gm., 0.048 mole) is mixed with pyridine hydrochloride (120 gm.) in a reaction vessel and heated in a metal bath at 195°-200° C. for 30 minutes. The mixture is cooled somewhat and poured with stirring into cold water (800 ml.). The solid that separates is removed by filtration and washed with water. After drying, the product is triturated with acetonitrile (80 ml.) at 60°, cooled, filtered and dried. The yield of crude 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one is 12.2 gm., m.p. 260°-265° C. This material is pure enough for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[C:18]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[C:25]([OH:27])=O)([CH3:21])([CH3:20])[CH3:19].[CH:36]1(N=C=NC2CCCCC2)CCCC[CH2:37]1>ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10]([NH:12][CH2:13][CH2:17][CH2:16][CH2:15][CH2:14][CH2:36][CH3:37])=[O:11])=[C:2]([NH:1][C:25](=[O:27])[C:24]2[CH:23]=[C:22]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:30]([OH:31])=[C:29]([C:32]([CH3:33])([CH3:35])[CH3:34])[CH:28]=2)[CH:7]=1
Reactant: Nc1cc(F)ccc1NC(=O)NC1CCCC1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccc(F)cc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 67.6 %

Procedure:
1-(2-amino-4-fluorophenyl)-3-cyclopentylurea (1.07 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (1.00 g) and dicyclohexylcarbodiimide (0.99 g) were stirred in dichloromethane (35 ml) at room temperature for 3 hrs. After filtering off the insolubles and distilling off the solvent, the residue was purified by a silica gel column chromatography (chloroform:ethyl acetate=10:1) to yield N-[5-fluoro-2-(3-heptylureido)phenyl]-3,5-di-t-butyl-4-hydroxybenzamide (1.35 g, 68%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([OH:20])=O)=[N:10]1.C1N=CN(C([N:28]2[CH:32]=NC=C2)=O)C=1.CN([CH:36]=[O:37])C.CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([N:28]([O:37][CH3:36])[CH3:32])=[O:20])=[N:10]1
Reactant: CN(C)C=O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cn(-c2cc(I)ccc2F)nc(C(=O)O)c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2cc(I)ccc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 50 °C
Reaction time: 1.17 h
Yield: 82 %

Procedure:
A mixture of 1-(2-fluoro-5-iodophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (9.96 g, 25.5 mmol) and CDI (4.55 g, 28.1 mmol) in THF (200 mL) was heated to 40° C. for 30 min and 50° C. for 90 min. To the mixture was added DMF (20 mL). The mixture was stirred at 50° C. for 70 min. To the solution were added N,0-dimethylhydroxylamine hydrochloride (3.74 g, 38.3 mmol) and i-Pr2NEt (6.67 mL, 38.3 mmol) at room temperature. The solution was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, diluted with water and 1 M HCl aqueous solution, extracted with EtOAc, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=20/80 to 0/100 and EtOAc/MeOH=100/0 to 0/100) and triturated with MeOH/EtOH/hexane to yield the title compound (9.11 g, 82% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.24 (3H, s), 3.56 (3H, s), 3.80 (3H, s), 7.36 (1H, dd, J=10.6, 8.7 Hz), 7.93 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 8.12 (1H, dd, J=7.4, 2.1 Hz), 8.53 (1H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].C(N(CC)CC)C.C1(O[C:28](Cl)=[O:29])C=CC=CC=1.[NH2:31][C:32]1[S:33][C:34]([Br:37])=[CH:35][N:36]=1>C(#N)C>[Br:37][C:34]1[S:33][C:32]([NH:31][C:28]([NH:13][S:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)(=[O:11])=[O:12])=[O:29])=[N:36][CH:35]=1
Reactant: NS(=O)(=O)c1cc2ccccc2[nH]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ncc(Br)s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Br)s1)NS(=O)(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a solution of 1H-indole-2-sulfonic acid amide (Graham, S., Hoffman, J. Med. Chem., 33(2), 749-754 (1990); 0.235 g, 1.2 mmol) in acetonitrile (15 mL) was added at 10° C. triethylamine (0.4 mL), followed dropwise over 5 minutes by a solution of chloroformic acid phenyl ester (0.22 g, 1.4 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at rt for 1 h and 2-amino-5-bromothiazole (0.225 g, 1.3 mmol) was added. The reaction mixture was stirred at 55° C. for 2 h. The precipitate that was formed was filtered off, washed with acetonitrile and ether and dried to obtain the title compound (0.18 g) as a pink solid. MS (ISN) m/e 399.0, 400.9 (M−H)−
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]3(C#N)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]=2[NH:11]1>>[C:1]1([C:21]2([N:18]3[CH2:19][CH2:20][CH:15]([N:14]4[C:13]5[CH:30]=[CH:31][CH:32]=[CH:33][C:12]=5[NH:11][C:10]4=[O:9])[CH2:16][CH2:17]3)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CCCCCC1
Product: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Yield: 56 %

Procedure:
This was prepared according to the procedure described in Example 1 using phenylmagnesium bromide and 1-[4-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidino]-1-cycloheptanecarbonitrile. Yield was 56%.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[NH2:6])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:17][CH2:18][C:19](Br)=[O:20]>CCOCC>[Br:17][CH2:18][C:19]([NH:6][C:5]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=1[C:1](=[O:3])[CH3:2])=[O:20]
Reactant: CC(=O)c1cccc(C)c1N
Reactant: O=C(Br)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1cccc(C)c1NC(=O)CBr
Temperature: 0 °C

Procedure:
To a mixture of 4.8 g of 2-acetyl-6-methylaniline, 3 g of sodium acetate and 120 ml of ether was simultaneously added a solution of 13.2 g of bromoacetyl bromide in 30 ml of ether and 60 g of ice at -3° to 0° C. for 15 minutes. The resultant mixture was stirred at 0° to 5° C. for 2 hours. The ether layer was separated, washed with an aqueous solution of sodium carbonate, dried over anhydrous sodium sulfate and evaporated to give 2-bromo-2'-acetyl-6'-methylacetanilide as crystals. m.p. 97° - 100° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:39][C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=2)[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Agent: Cl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)cc3)cn2)c1
Yield: 70.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.62 g) and 2-(chloromethyl)-4-methylpyridine hydrochloride (0.46 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[OH:7][C:8]1[N:13]=[C:12]([OH:14])[C:11]([F:15])=[CH:10][N:9]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.CN(C)C=O>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[CH:10]=[C:11]([F:15])[C:12](=[O:14])[NH:13][C:8]1=[O:7]
Reactant: Oc1ncc(F)c(O)n1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCCl)cc1F
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to a solution of 1.95 g (15.0 mmol) of 2,4-dihydroxy-5-fluoropyrimidine in 50 ml of dimethyl sulfoxide and 20.0 ml of N,N-dimethylformamide (DMF) at 0° C. 2.07 g (15.0 mmol) of K2CO3 were added in portions over the course of 1 hour, and the mixture was stirred at 20° C. for 1 hour (dialkylated product already identifiable). Water was then added to the reaction mixture, and the aqueous mixture was extracted twice with diethyl ether and twice with methylene chloride. The aqueous phase was adjusted to pH 3-4 with hydrochloric acid and then the aqueous phase was extracted with methylene chloride. The organic phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 0.6 g.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:17])=[CH:9][CH:8]=1)#[N:6]>O.Cl>[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][NH2:1])=[CH:9][CH:8]=1)#[N:6]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NN)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4.09 g of sodium nitrite in 30 ml of water is added to a solution, cooled to 0° C., of 8.35 g of 4-cyano-1-naphthylamine in 180 ml of 1N HCl. The mixture is left stirring for 1 hour 15 minutes at 0° C. It is cooled to -10° C., and a solution of 41.75 g of stannous chloride dihydrate in 42 ml of concentrated HCl is added slowly. The reaction mixture is stirred for 1 hour, allowing the temperature to rise to RT. It is filtered. The residue is suspended in water and 20 ml of concentrated NaOH are added. The expected product is obtained after filtration, rinses with water and then drying under vacuum, m =8.6 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.1 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (7 g, 0.032 mol) in 3 mL of NMP, KOH (12.7 g, 0.226 mol) was added at RT. The reaction mixture was stirred well at RT for 20 min. Then a solution of 2-bromo-1-(4-fluorophenyl)ethanone (6.5 g, 0.032 mol) in 2 mL NMP was added dropwise into the reaction mixture at RT over 2-4 h. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography, providing the desired product (1.2 g, 11.02%). 1HNMR (CDCl3, TFA salt) d (ppm): 8.18-8.01 (m, 2H), 7.71 (s, 1H), 7.30 (s, 1H), 7.22-7.10 (m, 2H), 7.00 (d, 1H), 3.60-3.31 (m, 4H), 3.20-3.06 (m, 2H), 2.85-2.70 (m, 2H), 2.45 (s, 6H).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)N)#[N:3].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>C(O)(=O)C.O>[C:2]([C:4]1[CH:5]=[CH:6][CH:8]=[CH:9][C:10]=1[S:15]([Cl:1])(=[O:17])=[O:16])#[N:3]
Reactant: N#Cc1cccc(N)c1
Reactant: O=S=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccccc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 200 ml of water and 250 ml of concentrated hydrochloric acid was added 25.0 g (212 mmol) of 3-cyanoaniline followed by stirring. An aqueous solution (80 ml) of 15.5 g (223 mmol) of sodium nitrite was added dropwise thereinto at −10° C. The reaction solution was added to acetic acid saturated with sulfur dioxide (prepared by saturating sulfur dioxide in 250 ml of acetic acid followed by adding 2.1 g of cuprous chloride) under ice-cooling and stirring. After 1 hour, the reaction solution was poured onto 500 ml of ice water and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and brine successively, and dried over magnesium sulfate. The solvent was evaporated, a mixed solution of diethyl ether and hexane was added to the residue and the crystals were collected by filtration to give 16.0 g of the title compound.
Reaction SMILES: [C:1](=O)(O)[O-:2].[Na+].Cl.[CH3:7][O:8][C:9](=[O:19])[C@@H:10]([NH2:18])[CH2:11][C:12]([F:17])([F:16])[CH2:13][CH2:14][CH3:15].[CH2:20]1[CH2:26][O:25][CH2:24][CH2:23][NH:22][CH2:21]1.Cl.C(N(CC)CC)C>C(#N)C>[CH3:7][O:8][C:9](=[O:19])[C@@H:10]([NH:18][C:1]([N:22]1[CH2:21][CH2:20][CH2:26][O:25][CH2:24][CH2:23]1)=[O:2])[CH2:11][C:12]([F:17])([F:16])[CH2:13][CH2:14][CH3:15]
Reactant: C1CNCCOC1
Reactant: CCCC(F)(F)C[C@H](N)C(=O)OC
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCCOCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
To a mixture of Sodium bicarbonate (5.25 g), p-nitro chloroformate (5.03 g, 25 mmol) in acetonitrile (130 mL) under nitrogen is added (S)-2-Amino-4,4-difluoro-heptanoic acid methyl ester hydrochloride (5.79 g, 0.025 mol) and stirred at room temperature for 5 hr. Homomorpholine hydrochloride (3.61 g, 26.25 mmol) and triethyl amine (12.5 mL) are added and the reaction stirred overnight at room temperature. Solvent evaporated off under reduced pressure, crude partitioned between water (150 mL) and ethyl acetate (200 mL). Organic layer separated, washed with K2CO3 solution (150 mL), HCl (150 mL) and brine (150 mL). Organic layer separated, dried (MgSO4) and evaporated under reduced pressure. Crude purified by column chromatography eluting with v/v 1:1 to 8:2 ethyl acetate heptane followed by ethyl acetate to give (S)-4,4-Difluoro-2-[(perhydro-1,4-oxazepine4-carbonyl)-amino]-heptanoic acid methyl ester (4.8 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]#[C:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:36][CH3:37].C(O)(=O)C.N>C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].O>[Br:1][C:2]1[C:3]([O:36][CH3:37])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:15]4[C:16](=[O:17])[N:18]([C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]=4[C:25]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[C:9]3[C:10]=2[CH:11]=1
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCOCC#Cc1cccs1)C(C)(C)C)CC2
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Temperature: 105 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A solution of 257 mg of 7j in a mixture of 5 ml of acetic anhydride and 100 mg of sodium acetate was heated at 105° C. for 30 min. The reaction mixture was cooled, diluted with 20 ml of water and stirred for 1 hr at RT. Then, acetic acid was neuralized by addition of cold conc. ammonia. The product was extracted with ethyl acetate and the organic layer was washed twice with water, dried, concentrated and the crude material was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate. The material isolated was triturated with diethyl ether, to give 120 mg of 7k;