Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.C(O[C:30]([N:32](C)[C@H:33]([CH3:37])[C:34](O)=[O:35])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:34](=[O:35])[C@H:33]([NH:32][CH3:30])[CH3:37])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1
Reactant: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: C[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN[C@H](C)C(=O)NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of Intermediate M (100 mg, 0.276 mmol), (R)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (67 mg, 0.33 mmol), TEA (0.115 mL, 0.828 mmol), and TBTU (106 mg, 0.331 mmol) in DMF (2 mL) is heated at 60° C. overnight. The reaction is diluted with EtOAc, rinsed with sat. NaHCO3, and the organics dried and concentrated. The residue is purified by silica gel chromatography eluting with 0-10% MeOH/DCM. The pooled and concentrated product fractions are treated with 4M HCl in 1,4-dioxane (5 mL) and stirred overnight. The reaction is concentrated and purified by reverse phase HPLC eluting with 10-90% MeCN in water (0.1% TFA). The concentrated product fractions are dissolved in MeOH and eluted through a carbonate resin cartridge to afford the title compound 261. (LC/MS method 16: ES+ m/z 411.4 [M+H]+, Rt=0.33 min)
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[N+:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12].[N+:24]([O-])([OH:26])=[O:25].ClC(Cl)C>>[N+:24]([C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]=1[N+:11]([O-:13])=[O:12])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(Cl)Cl
Solvent: c1ccc2ccccc2c1
Product: O=[N+]([O-])c1ccc2ccccc2c1[N+](=O)[O-]

Procedure:
DE-OS-24 53 529 describes the production of dinitronaphthalenes by nitration of naphthalene or 1-nitronaphthalene with nitric acid in an organic solvent, e.g., dichloroethane, with the azeotropic removal of the water of reaction. This process yields dinitronaphthalene in high yields, but without influencing the isomer ratio.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O1CCOCC1>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[NH:18][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:9])=[CH:11][CH:12]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Nc2cnccn2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
The mixture of 100 mg of the t-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate [106-1], 38 mg of 2-aminopyrazine, 6.8 mg of tris(dibenzylideneacetone)(chloroform)dipalladium (0), 7.7 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 217 mg of cesium carbonate, and 3 mL of 1,4-dioxane, was stirred overnight at 100° C. After cooling the reaction mixture back to room temperature, the insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by silica gel chromatography, to obtain 50 mg of t-butyl {(1S)-1-[4-(pyrazin-2-ylamino)phenyl]ethyl}carbamate [106-2] as a pale yellow solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[Cl:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][NH:37]2)=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][N:37]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ccc(Cl)cc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 63 mg (0.37 mmol) 6-chloro-2,3-dihydro-1H-indole, 0.15 mL (0.87 mmol) DIPEA and 130.00 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred for 1 h at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and suction filtered. The precipitate was dried under HV.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Br[C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=1>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3cc(F)c(F)c(F)c3)CC2)CC1

Procedure:
Using 4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexanone and 1-bromo-3,4,5-trifluorobenzene as starting raw materials, 1-(trans-4-propylcyclohexyl)-2-[trans-4-(3,4,5-trifluorophenyl)cyclohexyl]ethane was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:30])[C@@H:20]([NH2:29])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].O.[C:37]([O:40][C:41]1[C:42]([CH3:50])=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45])(=[O:39])[CH3:38]>C(OCC)(=O)C>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:30])[C@@H:20]([NH:29][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[C:41]([O:40][C:37](=[O:39])[CH3:38])[C:42]=1[CH3:50])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)CSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)N[C@@H](CSc2ccccc2)[C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)c1C
Yield: 101.1 %

Procedure:
(3S, 4aS, 8aS)-2-((2R, 3R)-3-Amino-2-hydroxy-4-phenylthiobutyl)-decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [14], 9.39 g) and sodium hydrogencarbonate (4.55 g, 54.2 mmol) were added to a suspension of water (40 ml) and ethyl acetate (40 ml). A solution of 3-acetoxy-2-methylbenzoyl chloride (4.37 g, 20.6 mmol) in ethyl acetate (40 ml) was dropwise added to the suspension with stirring under ice-cooling. The mixture was further stirred for one hour under ice-cooling and water (20 ml) was added. The organic layer was separated and washed with a saturated aqueous solution (20 ml) of sodium hydrogencarbonate. After drying over magnesium sulfate, the solvent was distilled away under reduced pressure to give (3S, 4aS, 8aS)-2-[(2R, 3R)-3-(3-acetoxy-2-methylbenzoylamino)-2-hydroxy-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid t-butylamide (12.7 g, yield 96%) as colorless amorphous. 1H-NMR (CDCl3, 300 MHz) δ: 7.5-7.1 (m,8H), 7.1-7.0 (m,1H), 5.51 (brd.s,1H), 4.48 (m,1H), 4.07 (m,1H), 3.81 (dd,J=13.7,9.2Hz,1H), 3.41 (dd,J=13.7,4.7Hz,1H), 2.91 (dd,J=11.7,2.0Hz,1H), 2.56 (dd, J=12.9,9.1Hz,1H), 2.44 (m,1H), 2.32 (s,3H), 2.27 (s,3H), 2.3-2.1 (m,2H), 1.99 (m,1H), 1.9-1.1 (m,11H), 1.07 (s,9H)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH:37][C:38]2[S:39][CH2:40][C:41](=[O:43])[N:42]=2)[CH2:31][CH2:30]1>>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:40]3[S:39][C:38]([NH:37][CH2:36][CH2:35][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:42][C:41]3=[O:43])=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1
Reactant: CN1CCN(CCNC2=NC(=O)CS2)CC1
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: CN1CCN(CCNC2=NC(=O)C(=Cc3ccc4c(c3)c(I)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and 2-[2-(4-Methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one following General Procedure E.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C=Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (0.05 g, 0.176 mmol), phenyl isocyanate (20.9 mg, 19.2 μL, 0.176 mmol) and N,N-diisopropylethylamine (68.1 mg, 92.0 μL, 0.527 mmol) were combined with CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hr. The crude product was purified using preparative reverse-phase HPLC, giving 1-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-phenyl-urea. MS calcd. for C23H19ClN3O2 [(M+H)+] 404.1 obsd. 403.9.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([N:29]3[CH2:30][CH2:31][N:27]([CH3:26])[C:28]3=[O:32])=[CH:9][C:6]=2[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C#N)CC2)c(C)c1
Yield: 83.7 %

Procedure:
Using 5-bromo-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]benzonitrile (398 mg) described in Preparation Example 188 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (349 mg) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37]([O:44][C:45](=[O:48])[CH2:46]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:46][C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:48])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g 4-{2-[(4-Hydroxy-quinoline-2-carbonyl)-amino]acetyl}-piperazine-1-carboxylic acid butyl ester in 41 ml of DMF, 8.6 g of cesium carbonate and 6.1 g of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 5.2 g.
Reaction SMILES: C(O)(=O)C.[ClH:5].Cl.[C:7]([NH:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:17]([OH:32])[CH:16]=1)=[O:14])([CH3:10])([CH3:9])[CH3:8]>CN(C)C=O>[ClH:5].[OH:32][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][C:22](=[O:31])[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH:13]([OH:14])[CH2:12][NH:11][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc(C(=O)Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Oc2ccc(C(O)CNC(C)(C)C)cc2O)cc1

Procedure:
Using a procedure similar to that described above in Example 58A, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 16 g. of sodium methoxide in 300 ml. of N,N-dimethylformamide under an atmosphere of nitrogen and then 17 g. of p-anisoyl chloride was added to produce 3-hydroxy-4-(p-anisoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride. This salt was converted to the free base which was treated with acetic acid to yield 35 g. of the acetate salt, m.p. 170°-175° C. (dec.)(uncorr.). By treating the salt in N,N-dimethylformamide with concentrated hydrochloric acid there was obtained 28 g. of the hydrochloride salt, m.p >235° C. (dec.)(uncorr.). When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:8][NH:9][C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:12]=2[CH:11]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][N:9]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:18])([F:19])[F:20])=[N:16][C:12]=2[CH:11]=1)[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5]
Reactant: CCCS(=O)(=O)Cl
Reactant: CNc1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N(C)c1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
Propane-1-sulfonyl chloride (27 uL, 34 mg, 0.24 mmol) was added to a solution of N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-amine (63 mg, 0.20 mmol) (see following steps B, C, D, E, F and G for preparation), DIPEA (49 uL, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (6 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with DCM (50 mL), washed with saturated NaHCO3 (2×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 40 mg (47%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 1.00 (t, J=7.42 Hz, 3 H), 1.38-1.53 (m, 4 H), 1.70-1.88 (m, 2 H), 2.15-2.30 (m, 1 H), 3.01-3.11 (m, 2 H), 3.28-3.33 (m, 2 H), 3.35 (s, 3 H), 3.88-3.91 (m, 2 H), 4.30 (d, J=7.62 Hz, 2 H), 7.55 (dd, J=8.79, 1.76 Hz, 1 H), 7.75 (d, J=8.98 Hz, 1 H), 7.82 (d, J=1.56 Hz, 1 H). MS (ESI) (M+H)+=420.0. Anal. Calcd for C18H24F3N3O3S+0.20 H2O+0.30 CH3OH (432.68): C, 50.80; H, 5.96; N, 9.71. Found: C, 50.79; H, 5.91; N, 9.69.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C(=C[C:39]([O:43]C)=CC=3)CC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][C:16]([O:43][CH3:39])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCc3cc(OC)ccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCc3cc(OC)ccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.29, 1.89, 2.56, 2.70, 2.83, 2.87, 3.00, 3.83, 4.49, 5.61, 6.81, 6.85, 7.23; HRMS (FAB) calcd for C18H22BrN3O+H 376.1025, found 376.1008.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:26][CH2:27][NH2:28]>CCCCC.CN(C=O)C>[CH2:3]([N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:26][CH2:27][NH2:28])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NCCCl
Reactant: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: NCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
Sodium hydride (60% in oil; 0.934 g, 23.36 mmol) is washed three times with pentane. DMF (5 mL) is added, followed by 9-benzyl-9H-Carbazol-4-ol (1.52 g, 5.56 mmol) dissolved in DMF (10 mL) added over 10 min. The mixture is stirred an additional 5 min and then cooled in an ice-water bath. A solution of 2-chloroethylamine hydrochloride (1.29 g, 11.12 mmol) dissolved in DMF (5 mL) is added dropwise over about 5 min. The cooling bath is removed and the mixture is allowed to stir at room temperature over the weekend. Aq. sodium bicarbonate is added and the mixture partitioned between EtOAc, brine, and aq. sodium bicarbonate. The organic layers are dried over MgSO4 and taken to dryness. The residue is chromatographed on silica gel (120 mL) using CH3OH—CH2Cl2 (4/96) to give 1.26 g (72%) of the title compound as a white solid. An aliquot is crystallized from CH2Cl2-EtOAc-hexane; IR (drift) 1597, 1587, 1458, 1441, 1342, 1329, 1269, 1156, 1145, 1110, 1045, 860, 785, 749, 726 cm−1; 1H NMR (CDCl3) δ3.30, 4.29, 5.51, 6.70, 7.00, 7.12, 7.2-7.4, 8.34. Anal. Calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 78.70; H, 6.41; N, 8.70.
Reaction SMILES: ClCC([NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=1)=O.NC(N)=S>C(O)(=O)C.C(O)C>[F:15][C:10]1[CH:9]=[C:8]([CH2:7][C:6]([NH2:5])([CH3:16])[CH3:17])[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: Cc1ccc(CC(C)(C)NC(=O)CCl)cc1F
Agent: NC(N)=S
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(CC(C)(C)N)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
2-Chloro-N-[1-(3-fluoro-4-methylphenyl)-2-methylpropan-2-yl]acetamide (131.6 g) obtained in Step 6 was dissolved in acetic acid (200 ml) and ethanol (1 L), and thiourea (46.6 g) was added. The mixture was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, and the precipitated crystals were filtered. The filtrate was concentrated under reduced pressure, and 4N-sodium hydroxide solution (300 ml) was added to the obtained residue. The mixture was extracted 3 times with toluene. The organic layer was washed with brine, and concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether (1 L) and 4N-hydrochloric acid/ethyl acetate solution (255 ml) was added dropwise under ice-cooling. The mixture was stirred for 1 hr and the precipitated crystals were collected by filtration. The obtained crystals were added to a mixture of toluene and 4N-aqueous sodium hydroxide solution. The toluene layer was separated, washed twice with water, and concentrated under reduced pressure to give the title compound (57.9 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:16][CH:15]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH:22]([NH:24][C:25](=[O:27])[CH3:26])[CH3:23])=[CH:18][CH:19]=2)=[CH:6][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: CC(C)Oc1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC(C)CCc1ccc(Oc2cc(OC(C)C)cnc2Cl)cc1

Procedure:
2,3-Dichloro-5-isopropoxypyridine (514 mg, 2.496 mmol) and N-[3-(4-hydroxy-phenyl)-1-methylpropyl]acetamide (517 mg, 2.496 mmol) were reacted with sodium hydride in DMF in analogy to example 2c. Yield: 29 mg (3%), M+H+: 377.09. The isomer N-{3-[4-(2-chloro-5-isopropoxypyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide was formed as further compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:10]([CH3:32])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.BrC1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=1>ClCCl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:24][S:21]([C:19]1[CH:18]=[CH:17][C:16]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[C:15]([C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)[CH2:9][CH:10]2[CH3:32])=[O:31])[CH:20]=1)(=[O:23])=[O:22]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of rac-4-(5-Methanesulfonyl-2-morpholin-4-yl-benzoyl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.54 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) and the reaction mixture was stirred at room temperature for 30 min. After such time the reaction mixture was concentrated in vacuo, and the residue was dissolved in toluene (5 ml). To the solution were added 1-Bromo-4-trifluoromethyl-benzene (0.15 ml, 1.1 mmol), sodium-tert butylate (128 mg, 1.4 mmol), 2-(dicyclohexylphosphino)biphenyl (3.8 mg, 0.011 mmol), and tris(dibenzylidene-acetone)dipalladium-chloroform complex (5.5 mg, 0.005 mmol). The reaction mixture was then stirred for 16 hours at 80° C. After allowing to cool to room temperature the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2, 70 g, dichloromethane/methanol 0-5%) to give the title compound (83 mg, 30%). MS (m/e): 512.3 (M+H+)