Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][OH:16].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:5]1([CH2:4][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[CH2:15][OH:16])[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCc1nc2ccccc2n1CC1CC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 25.8 %

Procedure:
To a solution of (bromomethyl)cyclopropane (0.39 mL, 4.02 mmol) and (1H-benzoimidazol-2-yl)-methanol (596 mg, 4.02 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (0.84 mL, 4.82 mmol). The reaction mixture was stirred at 60° C. for 3 days. Then it was cooled to room temperature and quenched with saturated NaHCO3 (15 mL) and the phases were separated. The aqueous phase was washed with CH2Cl2 (3×20 mL). Then the combined organic layers were washed with brine (2×30 mL), dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a dark brown oil. Purification by flash column chromatography on silica gel using 2% CH3OH/CH2Cl2 afforded the product as a yellow solid (210 mg, 26%). 1H NMR (CDCl3) δ 0.40-0.45 (m, 2H), 0.52-0.61 (m, 2H), 1.22-1.33 (m, 1H), 4.13 (d, 2H, J=6.6 Hz), 4.88 (s, 2H), 7.22-7.24 (m, 2H), 7.36-7.38 (m, 1H), 7.66-7.69 (m, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:12][CH2:11][C@H:10]([CH3:9])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CCC[C@@H](C)CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)CCBr
Temperature: 25 °C
Yield: 87.3 %

Procedure:
5.65 g (31.8 mmol) of N-bromosuccinimide are added portionwise while stirring to a solution of 5 g (31.6 mmol) of (R)-3,7-dimethyl-1-octanol and 9.05 g (34.5 mmol) of triphenylphosphine in 20 ml of methylene chloride. The temperature is held below 25° by occasional cooling of the reaction vessel. After 30-minutes stirring at room temperature, the solvent is removed on the rotary evaporator. The residue is washed out several times with n-hexane, then filtered and again rinsed with n-hexane. The combined n-hexane phases are concentrated on the rotary evaporator and the crude product is chromatographed on 200 g of silicagel with n-hexane. Distillation in the bulb-tube at 105°/15 Torr gives 6.1 g (87%) of (R)-1-bromo-3,7-dimethyloctane; [α]D20 = -5.0 (c = 0.82, CHCl3).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:38]N1C(=O)CCC1=O>>[C:18]([O:17][C:12]1[CH:13]=[C:14]([CH2:16][Br:38])[CH:15]=[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OC(=O)c2ccccc2)cc(OC(=O)c2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C(Oc1cc(CBr)cc(OC(=O)c2ccccc2)c1)c1ccccc1

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 11 using 24.93 g (0.075 mol) of 5-methyl-benzene-1,3-diol dibenzoate, a catalytic amount of 2,2'-azobisisobutyronitrile and 13.35 g (0.075 mol) of N-bromosuccinimide. Recrystallization of the crude material from ethyl acetate gave a product (m.p. 123°-126° C.) which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)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]>[Cl:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([CH3:11])[N:9]=[CH:8][CH:7]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: O=Cc1c(Cl)ccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nccc(Cl)c1C=O
Temperature: 100 °C
Yield: 16.4 %

Procedure:
A mixture of 2,4-dichloronicotinaldehyde (1.1 g, 6.25 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.942 g, 7.50 mmol), Cs2CO3 (6.11 g, 18.75 mmol) and PdCl2(dppf) (0.229 g, 0.312 mmol) in 1,4-dioxane (9 mL) and water (1 mL) was heated at 100° C. for 18 h. After cooling, the mixture was diluted with ethyl acetate (15 mL) and water (20 mL). The ethyl acetate layer was dried over Na2SO4, concentrated and purified by silica gel chromatography to afford 4-chloro-2-methylnicotinaldehyde (0.16 g, 1.028 mmol, 16% yield) as a yellow solid 1H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 8.52 (d, J=7.2 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 2.83 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([CH2:17]OS(C)(=O)=O)[CH2:3]1.[CH3:23][N:24](C=O)C.[C-]#N.[Na+]>O>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([CH2:17][C:23]#[N:24])[CH2:3]1
Reactant: CS(=O)(=O)OCC1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCC1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Temperature: 52.5 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
A mixture of methanesulfonic acid 5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl ester (prepared as given in Example B1)(0.9 g, 2.66 mmol), DMF (5 ml) and sodium cyanide (0.19 g, 4.0 mol) were heated to 50-55° C. and stirred for 20 hrs. To this reaction mixture water (50 ml) was added and extracted with ethyl acetate (3×20 ml), organic layer was washed with saturated brine solution (20 ml). The organic layer was dried over Na2SO4 and evaporated to obtain [5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-acetonitrile (0.65 g, 91%) as brownish sticky mass.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[C:24]([O:31][CH3:32])=[N:25][C:26]([Cl:30])=[C:27]([Cl:29])[CH:28]=2)=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[C:24]([O:31][CH3:32])=[N:25][C:26]([Cl:30])=[C:27]([Cl:29])[CH:28]=1)[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Cl)c(Cl)nc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((5,6-dichloro-2-methoxypyridin-3-yl)amino)phenyl)acrylate (2.54 g, 5.19 mmol) and MeOH (25.9 ml) to give a yellow suspension. Sodium methoxide, 0.5M solution in methanol (4.15 ml, 2.076 mmol) was added. A reflux condenser was attached, and the reaction was heated to 70° C. and stirred overnight. The reaction was cooled to RT and filtered through a pad of Celite/silica gel and then washed with MeOH and then with DCM. The reaction was concentrated, dissolved in IPA, and heated to 110° C. The solution was filtered, cooled to RT, and concentrated to afford 6-(benzylthio)-1-(5,6-dichloro-2-methoxypyridin-3-yl)quinolin-2(1H)-one (2.10 g, 4.74 mmol, 91% yield) as a light yellow solid. m/z (ESI) 443.0 (M+H)+.
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CS(O[CH2:13][CH2:14][CH:15]1[CH2:19][C:18]2[CH:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=[CH:23][C:17]=2[O:16]1)(=O)=O>>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][CH:15]1[CH2:19][C:18]2[CH:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:22]=[CH:23][C:17]=2[O:16]1
Reactant: C[C@H]1CCCN1
Reactant: CS(=O)(=O)OCCC1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Agent: Br
Product: C[C@@H]1CCCN1CCC1Cc2cc(-c3ccc(C#N)cc3)ccc2O1

Procedure:
(2S)-2-Methylpyrrolidine hydrobromide and the product from Example 67D are processed as described in Example 1D to provide the titled compound.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH3:10])([O-:9])=[O:8].N1([C:20](=[O:33])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)C2C=CC=CC=2N=N1.O>CS(C)=O.C(O)(=O)C>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[O:22][CH2:21][C:20](=[O:33])[CH2:10][N+:7]([O-:9])=[O:8]
Reactant: COc1ccc(OCC(=O)n2nnc3ccccc32)cc1OC
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OCC(=O)C[N+](=O)[O-])cc1OC
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a suspension of potassium tert-butoxide (3.38 g) in DMSO (60 ml), a solution of nitromethane (0.836 g) in DMSO (5 ml) was added at 10° C. and the mixture was stirred at the same temperature for 30 minutes. A DMSO (65 ml) suspension of the compound (4.30 g) obtained in Example 19-(1) was added dropwise at 10° C. and the mixture was stirred at the same temperature for an hour, then at room temperature for 3 hours. The reaction mixture was poured into water (250 ml), rendered acidic with 10% aqueous acetic acid, and subjected to extraction with AcOEt. The organic layer was washed with water, dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) and then recrystallized (AcOEt/hexane) to give the titled compound (0.808 g, pale yellow solid.)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[C:5]([C:19]#[N:20])=[CH:4][CH:3]=1.ClCCl.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:19]([C:5]1[C:6]([CH3:18])=[C:7]([C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])#[N:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(C#N)ccc(N)c1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C#N)ccc(NS(=O)(=O)c2ccccc2)c1C(=O)OCc1ccccc1

Procedure:
A mixture of Example 108B (576 mg, 2.2 mmol), anhydrous dichloromethane (22 mL), pyridine (0.4 mL) and benzenesulfonyl chloride (0.33 mL) was stirred 18 hours under nitrogen atmosphere. The mixture was concentrated, dissolved in ethyl acetate (100 mL), washed with 0.5M HCl (3×50 mL) and brine, dried (Na2SO4), filtered, concentrated, and purified on silica gel (20 g) with 50% dichloromethane in hexanes to provide the desired product. MS (ESI(+)) m/e 407 (M+H)+, 424 (M+NH4)+, 429 (M+Na)+; (ESI(−)) m/e 405 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.59 (br s, 1H), 7.77 (m, 3H), 7.64 (m, 1H), 7.56-7.37 (m, 7H), 7.24 (d, 1H), 5.31 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: [CH:1]([OH:40])([CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:39])([F:38])[F:37])([F:35])[F:34])([F:32])[F:31])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23])[CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4].[C:41]1(=[O:47])[O:46][C:44](=[O:45])[CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH:1]([O:40][C:41]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[O:47])([CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4])[CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:37])([F:39])[F:38])([F:34])[F:35])([F:31])[F:32])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23]
Reactant: O=C1CCC(=O)O1
Reactant: CN(CC(O)CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CN(CC(CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OC(=O)CCC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A 250 mL three necked round bottom was charged with [C4F9SO2N(CH3)CH2]2CHOH (6.8 g; 10 mmole), succinic anhydride 1.0 g; 10 mmole) 4-dimethylaminopyridine (0.1 g) and toluene (100 mL). The ensuing mixture was stirred at 100° C. overnight, the toluene removed using a rotary evaporator, leaving a white solid residue that was triturated with toluene-hexane to yield [C4F9SO2N(CH3)CH2]2CHOC(O)C2H4COOH (5.2 g)
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].IC.O>CN1C(=O)CCC1>[Br:1][C:2]1[C:11]([O:12][CH3:14])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2ccc(Br)c(O)c2n1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1c(Br)ccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98.1 %

Procedure:
To a solution of 7-bromo-2-methylquinolin-8-ol (4.10 g, 14.64 mmol) and Cs2CO3 (11.92 g, 36.59 mmol) in NMP (20 mL) was added iodomethane (1.01 mL, 16.10 mmol) at 0° C. The reaction was warmed to ambient temperature and stirred at ambient temperature for 40 minutes. Water (30 mL) was and added and extracted with DCM (30 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM) to give 7-bromo-8-methoxy-2-methylquinoline (3.62 g, 91.23%) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:12]([O:16][C:17](=[O:24])[NH:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Yield: 84.2 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (1 g), pyrrolidin-3-ylcarbamic acid tert-butyl ester (1.2 g), potassium carbonate (1.79 g) and dimethyl sulfoxide (10 ml) were heated together at 80° C. under nitrogen for 15 h. The mixture was then cooled, diluted with ethyl acetate (200 ml), washed with 2N aqueous hydrochloric acid (200 ml), dried (MgSO4) then concentrated. Purification of the residue by silica gel chromatography (eluting with 20% ethyl acetate in isohexane) gave the subtitle compound (1.744 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21](Br)=[CH:22][CH:23]=2)[C@H:18]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][C@@H:16]1[CH2:33][CH3:34])(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:22][CH:23]=2)[C@H:18]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][C@@H:16]1[CH2:33][CH3:34])(=[O:14])[CH3:13]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(Br)ccc2N1C(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(C=O)cc3)ccc2N1C(C)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A mixture of (4-formylphenyl)boronic acid (31.7 mg, 0.212 mmol), (cis)-1-acetyl-6-bromo-2-ethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 90) (79 mg, 0.212 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was treated with potassium carbonate (45 mg, 0.326 mmol) and the resulting mixture was stirred at 130° C. for 15 min under microwave irradiation then cooled to room temperature and concentrated in vacuovacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient:0 to 100% AcOEt in Hexanes) gave 4-[(cis)-1-acetyl-2-ethyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzaldehyde (67.8 mg, 0.17 mmol, 80%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:18][CH2:19]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: COc1ccccc1N1CCN(CCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: COc1ccccc1N1CCN(CCNc2ccccc2[N+](=O)[O-])CC1
Reaction time: 32 h
Yield: 32.1 %

Procedure:
A mixture of 3.03 g of 2-chloronitrobenzene, 4.52 g of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine, and 3.18 g of anhydrous potassium carbonate in 30 mL of n-butanol was stirred for 32 h at reflux. After cooling, the mixture was poured into H2O, then extracted with EtOAc and the organic phase dried on Na2SO4. The crude obtained by evaporating the solvent was purified by flash chromatography (EtOAc-petrolium ether 4:6) and the residue obtained after evaporation of the solvents was taken up with Et2O, stirred and filtered giving 2.2 g (31%) of the title compound. Melting point: 117-118° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.COP(O)([O:13][CH3:14])=O.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27]C=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>C1COCC1>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:14]([OH:13])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2ccccc2)cc1
Reactant: COP(=O)(O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of LDA [prepared from diisopropylamine (3.5 mL, 24.5 mmol) and 2.2M n-butyllithium in hexanes (12 mL, 26.4 mmol)] in THF (120 mL) at −78° C. was added a solution of 4′-methyl-biphenyl dimethyl phosphate (6.1 g, 20.9 mmol) in THF (20 mL). The mixture was stirred at −78° C. for 1 h and then at r.t. for 1 h. After quenching with 2M aqueous HOAc (10 mL), solvent was removed in vacuo. The residue was diluted with H2O and extracted with EtOAc. The EtOAc extract was washed with H2O (2×), dried (MgSO4) and concentrated. Chromatography over silica gel and elution with hexanes:EtOAc (3:2) provided 1.3 g of 4′-methyl-4-hydroxybiphenyl. Further elution gave 4.0 g (65.5%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51]2[N:54]=[C:55]([NH2:57])[S:56][C:50]=2[CH:49]1[C:58]1[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=1[O:65][CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51]2[N:54]=[C:55]([NH:57][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])[S:56][C:50]=2[CH:49]1[C:58]1[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=1[O:65][CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)C1CC1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(N)nc2CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(NC(=O)C3CC3)nc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclopropanecarboxylic acid (5 μL, 60 μmol, 1 eq.) in DMF (5 mL), DIPEA (51 μL, 300 μmol, 5 eq.) and TBTU (19 mg, 60 μmol, 1 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 minutes. Then (±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (30 mg, 60 μmol, 1 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[C:51]([F:53])[CH:52]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH:26]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)=[CH:20][C:19]=1[N:37]([CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)C(=O)C(F)(F)F)=[O:17]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[C:51]([F:53])[CH:52]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH:26]2[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[CH2:29]2)=[CH:20][C:19]=1[NH:37][CH:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC(CNc2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CNc2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)C1

Procedure:
tert-butyl 3-{[(4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]phenyl)amino]methyl}azetidine-1-carboxylate (760 mg, 1.02 mmol) was dissolved in MeOH (12 mL) and TEA (4 mL) and stirred at room temperature overnight. Volatiles were evaporated and the residue was taken-up with DCM and washed with brine. Organic phase was dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][OH:25])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.9 %

Procedure:
1.00 g (3.30 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 0.49 g (3.92 mmol) of 2-bromoethanol were dissolved in 10 ml of acetone, and 0.55 g (3.98 mmol) of potassium carbonate was added to the mixed solution. The mixture was stirred at room temperature for 15 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a mixture of chloroform and methanol in the volume ratio 20:1 as the eluent. The desired fraction was concentrated under reduced pressure to give 0.64 g (56%) of 2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethanol as an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24].O>ClCCl>[Br:15][C:16]1[C:17]([O:23][CH3:24])=[CH:18][C:19]([F:22])=[C:20]([C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([F:5])[CH:7]=2)=[O:10])[CH:21]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1cc(F)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(F)c(C(=O)c2cccc(F)c2)cc1Br
Temperature: -60 °C

Procedure:
A total of 716 mg of aluminium chloride was suspended in 24.4 ml of dichloromethane and was then mixed with 0.65 ml of 3-fluorobenzoyl chloride and 1 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a under stirring at −60° C. The mixture was raised in temperature to room temperature over 2.5 hours and was stirred for further 3 hours. Water was added to the reaction mixture under ice-cooling, followed by extracting with diethyl ether. The resulting organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 856 mg of the title compound as white crystals.