Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(OCC)(=O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:3][C:2]=1[Br:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])c(Br)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To tert-butyl N-(3-bromo-4-nitro-phenyl)carbamate (1 g, 3.15 mmol) in ethyl acetate (20 mL) is added tin (II) chloride dihydrate (3.56 g, 15.77 mmol) and stirred overnight at r.t. The reaction mixture is basified with potassium carbonate/sodium hydroxide. The organic layer is separated, dried and concentrated. The crude product is used without further purification for the next step. Yield 83%, m/z 287/289[M+H]+, rt 0.58 min, LC-MS Method X011_S03.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3]
Reactant: CCC(=O)Cl
Reactant: N#Cc1c(OCC2CCNC2)cccc1[N+](=O)[O-]
Agent: Cl
Product: CCC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)C1

Procedure:
Prepared as in Example 176b from 2-nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrile hydrochloride (Example 196d) and propionyl chloride in 51% as a yellow solid. MS 304 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)[CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C[C@H]1CC[C@H](CNC2C=CC(F)=C(F)C=2)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:31][C:26]1[CH:25]=[C:24]([N:15]([CH2:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([CH3:23])[CH2:21][CH2:22]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C[C@H]2CC[C@H](C)CC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: C[C@H]1CC[C@H](CNc2ccc(F)c(F)c2)CC1
Product: C[C@H]1CC[C@H](CN(C(=O)Nc2ncc(SCC(=O)O)s2)c2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared via {2-[3-(3,4-difluoro-phenyl)-3-(trans-4-methyl-cyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using trans-4-methyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6](I)[C:5]([CH3:13])=[N:4]1)[CH3:2].[Cu][C:15]#[N:16].CCOC(C)=O>CN(C=O)C>[C:15]([C:6]1[C:5]([CH3:13])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:16]
Reactant: CCn1nc(C)c(I)c1C(=O)OC
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1nc(C)c(C#N)c1C(=O)OC
Yield: 91.4 %

Procedure:
To a flask, methyl 1-ethyl-4-iodo-3-methylpyrazol-5-ylcarboxylate (1.00 g, 0.003 mol) was dissolved in 10 mL of DMF and copper (I) cyanide (0.46 g, 0.005 mol) was added in batches. After heating to reflux for 1 h, the mixture was separated by filtration. The filtrate was diluted with 50 mL of water, and then extracted with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution and 50 mL of saturated brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Column chromatography (EtOAc:P.E.=1:10 as eluent) gave 0.53 g of the title compound as a yellow oil (yield 80%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[CH2:12]([O:14][CH:15](OCC)[O:16][CH2:17][CH3:18])[CH3:13]>>[CH2:12]([O:14][CH:15]([O:16][CH2:17][CH3:18])[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1)[CH3:13]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)n1cc(C#N)c2ccccc21
Yield: 86 %

Procedure:
1H-Indole-3-carbonitrile (5.07 g, 35.7 mmol) was heated with triethylorthoformate (60 mL) in a pressure vessel at 160° C. for 3 d. Upon cooling, the solvent was evaporated and the residue was submitted to chromatography (20% ether in hexanes) to afford the title compound (7.46 g, 86%). NMR (300 MHz, CDCl3, 8): 7.92 (s, 1H), 7.76 (m, 1H), 7.62 (m, 1H), 7.32 (m, 2H), 6.23 (s, 1H), 3.63 (m, 4H), 1.23 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].CO.[OH-].[Na+]>O>[CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylate (110 mg, 0.30 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (60 mg, 1.50 mmol, 5.00 equiv), and water (2 mL). The resulting solution was stirred for 5 hr at 50° C. in an oil bath. The resulting mixture was concentrated in vacuo and diluted with 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with aq. hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 50 mg (46%) of 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[CH3:15].[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C1CCCCC1>[CH:16]([NH:20][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([CH3:15])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])([CH2:18][CH3:19])[CH3:17]
Reactant: CCC(C)N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Solvent: C1CCCCC1
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 10.04 g. (0.04 mole) of 2,4-dichloro-3,5-dinitrotoluene, 5.85 g. (0.08 mole) of sec-butylamine and 200 ml. of cyclohexane is stirred at reflux for six hours. The mixture is filtered and the filtrate is evaporated at reduced pressure. The filtrate is partitioned between ether and dilute hydrochloric acid. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. Crystallization of the residue from ethanol gives 7.71 g. of orange crystals, m.p. 40°-46° C. Two recrystallizations from ethanol give the analytical sample, m.p. 45°-47° C. Analysis Calcd. for C11H14ClN3O4 : C, 45.92; H, 4.90; Cl, 12.32; N, 14.61. Found: C, 45.96; H, 4.97; Cl, 12.36; N, 14.78.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:24]([O:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[CH3:25].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:31](=[O:32])[CH2:30][NH:29][C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)NCC(=O)O
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CNC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A mixture of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (173 mg, 0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488 mmol), EDCl (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate (161 mg); HPLC retention time=1.16 minutes (condition B); MS (m+1)=447.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.07 Hz, 3H) 1.29 (t, J=7.07 Hz, 3H) 2.50 (A of ABX, Jab=16.2 Hz, Jax=5.3 Hz, 1H) 2.54 (B of ABX, Jab=16.2 Hz, Jbx=5.3 Hz, 1H) 2.89 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1H) 3.80 (be d, J=5.8 Hz, 2H) 4.12-4.23 (m, 4H) 4.48-4.56 (m, 1H) 5.15 (br s, 1H) 6.64 (br d, J=8.8 Hz, 1H) 7.25-7.27 (m, 2H) 7.29-7.38 (m, 2H) 7.43-7.46 (m, 1H) 7.49-7.52 (m, 2H) 7.55-7.56 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[NH2:24][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:6][CH:7]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(C(=O)CC(C)C)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(C(N)CC(C)C)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-(3-Methyl-butyryl)-benzoic acid ethyl ester (2000 mg, 8.536 mM), ammonium acetate (6580 mg, 85.4 mM) and sodium cyanoborohydride (1070 mg, 17.1 mmol) in methanol (17.1 mL) was heated to 60° C. for 6 h. The reaction was cooled, quenched with NH4Cl solution (10 mL). MeOH was removed under reduced pressure. The aqueous solution was extracted with EtOAc (3×30 mL). The organic solution was separated, dried (Na2SO4) and concentrated. The crude material was separated by a 40 g HC silica gel column with 0-15% MeOH in DCM. The desired product was collected as colorless oily material (1560 mg, 77.7%). 1H NMR (500 MHz, CDCl3) δ ppm 0.91 (dd, J=13.66, 6.59 Hz, 6 H) 1.40 (t, J=7.07 Hz, 3 H) 1.84-1.99 (m, 3 H) 4.27-4.42 (m, 3 H) 6.36 (br. s., 2 H) 7.51 (d, J=8.05 Hz, 2 H) 8.05 (d, J=8.05 Hz, 2 H). GC: m/z 235.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[N:20]=[C:19](S(C)(=O)=O)[N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>C(O)CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[N:20]=[C:19]([O:23][CH2:22][CH2:21][OH:32])[N:18]=2)(=[O:14])=[O:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCOC1CCCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: OCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(OCCO)nc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
##STR149## (1) To ethylene glycol (2 ml) is added sodium hydride (60% dispersion, 125.8 mg). To this mixture is added 4-tert-butyl-N-{5-(2-methoxyphenoxy)-2-methylsulfonyl-6-[2-(tetrahydropyran-2-yloxy)ethoxy]pyrimidin-4-yl}benzene-sulfonamide obtained in Reference Example 10-(2) (500 mg), and the mixture is stirred at room temperature for 18 hours. To the reaction solution is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=1:1) to give 4-tert-butyl-N-{2-(2-hydroxyethoxy)-5-(2-methoxy-phenoxy)-6-[2-(tetrahydropyran-2-yloxy)ethoxy]pyrimidin-4-yl}benzene-sulfonamide (440.5 mg) as a colorless caramel.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([N+:26]([O-:28])=[O:27])[CH:34]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with (3-nitrophenyl)boronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-3-isopropyl-4-(3′-nitro-biphenyl-3-yl)-imidazolidin-2-one as a light yellow oil. MS: 466.0 ([M+H]+)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1COCC1.C(N(C(C)C)CC)(C)C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:19]2[CH2:20][CH2:21][CH:16]([CH2:15][OH:14])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1

Procedure:
Prepared in identical fashion to the 4-carboxamide analog by reacting 4-nitrobenzenesulfonyl chloride with 4-hydroxymethylpiperidine in THF containing 1 equivalent of diisopropyethylamine overnight at ambient temperature.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][CH2:29][N:28]=[C:27]1[NH2:31].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[NH:28]1[CH2:29][CH2:30][N:26]=[C:27]1[NH:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: NC1=NCCN1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3=NCCN3)c2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1), hydrogen iodide salt of 4,5-dihydro-1H-imidazol-2-amine (110 mg, 0.515 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.043 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), cesium carbonate (525 mg, 1.6 mmol) and 1,4-dioxane (3 mL) was heated with stirring in a 5 mL of microwave process vial for 2 hours at 120° C. under microwave irradiation. The resulting mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the product as a solid. MS obsd. (ESI+) [(M+H)+] 422, 1H NMR (400 MHz, CD3OD) δ ppm 7.68-7.59 (m, 2 H), 7.56 (s, 1 H), 7.50-7.41 (m, 2 H), 7.08 (s, 1 H), 5.23 (brs, 2 H), 4.62 (s, 3 H), 3.76 (s, 3 H), 3.61 (t, J=4.93 Hz, 2 H), 2.68 (s, 4 H), 2.45 (s, 2 H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1.CCN(CC)CC>CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1)=[O:1]
Reactant: COC(=O)C1CCCC(CO)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a cold (−78° C.) solution of 3-(methoxycarbonyl)cyclohexanecarboxylic acid (1.25 g, 6.71 mmol) in THF (20 mL) was added BH3.Me2S (0.7 mL, 7.38 mmol). The resulting mixture was stirred at −78° C. to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-(hydroxymethyl)cyclohexanecarboxylate as a colorless oil (845 mg, yield; 73%). To a solution of methyl 3-(hydroxymethyl)cyclohexanecarboxylate (840 mg, 4.88 mmol) in Et3N (4.4 mL, 32 mmol) and DMSO (10 mL) was added sulfur trioxide-pyridine complex (2.56 g, 16.1 mmol). The mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-formylcyclohexanecarboxylate as a pale yellow oil (795 mg, yield; 96%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]([C:27]#[N:28])[N:10]=1>COCCOC>[N:1]1([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27]#[N:28])[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2c(-n3ccnc3)nc(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of imidazole (15 mg) in 2 mL DME was added NaH (12 mg, 60% dispersion in mineral oil); a precipitate formed immediately. The mixture was stirred at room temp for 5 min, then heated to 75 C. A solution of 1-chloro-4-phenyl-6-methoxyisoquinoline-3-carbonitrile (60 mg) in 1 mL DME was added via cannula. Heating continued at 75 C for 45 min. The reaction was cooled to room temp and quenched by adding a few drops of water, then partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic solution was washed with brine (1×), dried over MgSO4 and concentrated. Flash chromatography (0% to 10% MeOH (10% NH4OH) in EtOAc) gave a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN1C(=O)CCC1>[CH3:17][S:16][C:13]1[N:14]=[CH:15][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=3[N:3]=[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]=2[N:12]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1nc(SC)ncc12
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1nc(SC)ncc12
Temperature: 120 °C

Procedure:
methyl 5-chloro-3-(methylthio)pyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 182 mg, 0.57 mmol) was mixed with aniline (0.5 ml) in NMP (1 ml). The mixture was heated under microwave for 10 minutes at 120° C. Water was added and the resulting solid was filtered and dried. The compound was triturated in EtOAc and hexanes and filtered to afford methyl 3-(methylthio)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate as a yellow solid. LCMS (ES): >95% pure, m/z 377 [M+1]+. This material was suspended in CH2Cl2 (4 ml) and meta-chloroperbenzoic acid (77% pure, 2.5 eq, 165 mg, 0.737 mmol) was added in small portions. After one hour, an additional amount (100 mg) of mcpba was added and the mixture stirred for 1.5 hours. After addition of more CH2Cl2, the organic phase was washed with water (4×), dried over Na2SO4 and the solution was filtered through a pad of silica gel, eluting with a MeOH/CH2Cl2 mixture. After evaporation of the solvents, methyl 3-(methylsulfonyl)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate was isolated as a yellow solid (166 mg, 72% yield). LCMS (ES): >95% pure, m/z 409 [M+1]+, 1H NMR (DMSO-d6, 400 MHz) δ 3.77 (s, 3H), 3.93 (s, 3H), 7.15 (t, J=7.2, 1H), 7.45 (t, J=7.6, 2H), 7.99 (dd, J=2.0, J=8.4, 1H), 8.16 (d, J=7.6, 2H), 8.28 (d, J=2.0, 1H), 8.89 (d, J=8.8, 1H), 9.76 (s, 1H), 10.61 (s, 1H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([NH2:6])[CH2:3]1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19]([NH:6][CH:4]1[CH2:5][N:2]([CH3:1])[CH2:3]1)=[O:20]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CN1CC(N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
To a solution of 1-methylazetidin-3-amine (1 equiv) in dry DCM (0.13 M) was added triethylamine (1.8 equiv). A solution of 3-methoxy-4-nitrobenzoyl chloride (0.91 equiv) in dry DCM was added and the reaction was stirred at room temperature for 5 min. The mixture was then concentrated and purified by silica gel chromatography (5% MeOH in DCM) to afford the title compound (46.4% yield) as a yellow solid. MS (ESI) m/z 266.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.C=O.[C:17](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.O>[CH3:2][O:3][C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([CH3:17])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc2c(c1)CCNCC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CCN(C)CC2
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (see EP 285287) (25 g, 125 mmol) and 37% formalin (25 mL) in dichloroethane (250 mL) was treated with sodium triacetoxyborohydride (30 g, 250 mmol) keeping the internal temperature below 20° C. After stirring for 2 h, water was added and the pH adjusted to 10 using 50% sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness to afford the product (23 g).