Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H](N)C(O)C1C=CC=CC=1.Cl.[BH4-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH:23]=[C:24]([N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].[N+]([O-])(O)=O>ClC1C=CC=CC=1.CN(C)C=O>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH:23]=[C:24]([N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)[CH:25]([OH:30])[C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1Cl)n1cncn1
Agent: C[C@@H](N)C(O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Solvent: Clc1ccccc1
Product: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1Cl)n1cncn1
Reaction time: 10 h
Yield: 100.3 %

Procedure:
To d-norephedrine hydrochloride (832 g) and monochlorobenzene (2,343 g), a dimethylformamide solution of sodium borohydride (166 g) was added, and the resultant mixture was stirred at a temperature of 20° to 30° C. for 1 hour. A monochlorobenzene solution of the E isomer of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl1-penten-3-one (991 g) was added thereto, followed by stirring at the same temperature as above for 10 hours. The reaction mixture was treated with dilute nitric acid. The monochlorobenzene layer was separated and concentrated to give the E isomer of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol (1,000 g) (content, 97.0%; yield, 97.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[C:3]=1[N+:16]([O-])=O>O1CCCC1.[Pt]=O>[CH2:8]([N:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([NH2:16])[C:4]1=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccn(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccccc2)c(=O)c1N

Procedure:
3.9 g (15.9 mmol) of 4-amino-1-benzyl-3-nitro-pyridin-2-one, dissolved in 250 ml of tetrahydrofuran, were hydrogenated over platinum oxide at 50 psi of H2 pressure and at ambient temperature. After the catalyst had been filtered off the filtrate was concentrated by evaporation and the residue was further processed in crude form.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C@@H:13]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C@H:14]([OH:18])[CH2:15][NH:16][CH3:17])[C:5]1=[O:26])[CH3:3].C(N1C2C=CC=CC=2N([C@@H](C2C=CC=C(F)C=2)[C@H](O)CO)C1=O)C>>[ClH:1].[CH2:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:14]([OH:18])[CH2:15][NH:16][CH3:17])[C:5]1=[O:26])[CH3:3]
Reactant: CCn1c(=O)n([C@@H](c2cccc(F)c2)[C@H](O)CNC)c2ccccc21
Agent: CCn1c(=O)n([C@@H](c2cccc(F)c2)[C@H](O)CO)c2ccccc21
Agent: Cl
Product: CCn1c(=O)n(C(c2cccc(F)c2)C(O)CNC)c2ccccc21

Procedure:
In an analogous manner to EXAMPLE 192, step 4 1-ethyl-3-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride was prepared from 1-ethyl-3-[(1S,2S)-2,3-dihydroxy-1-(3-fluorophenyl)-propyl]-1,3-dihydro-2H-benzimidazol-2-one as a white solid. MS (ES) m/z 344.2
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:3]1.[NH4+].[Cl-].C[OH:24]>>[OH:1][C:2]1([OH:24])[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:3]1
Reactant: CO
Reactant: COC(=O)c1cc(C(=O)OC)cc(N2CCC(=O)C2)c1
Agent: [Cl-]
Agent: [NH4+]
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCC(O)(O)C2)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
Dimethyl 5-(3-oxopyrrolidin-1-yl)isophthalate (0.1114 g, 0.401 mmol, 1 eq) and NH4Cl (0.086 g, 1.61 mmol, 4 eq) in 5 ml anhydrous MeOH were heated to reflux at 80° C. for 22 h. After cooling to room temperature the solvent was removed in vacuo. The residue was stirred in EtOH and filtered through cotton to remove any insoluble material. Purification via flash chromatography yielded 0.082 g, (0.25 mmol, 63% yield) of dimethyl 5-(3,3-dihydroxypyrrolidin-1-yl)isophthalate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH2:30][CH2:29]2)(=[O:25])=[O:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:34][CH:33]=4)[CH2:29][CH2:30]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N3CCc4cc(S(C)(=O)=O)ccc43)cc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl-4-(4-bromophenoxy)piperidine-1-carboxylate and 5-(methylsulfonyl)indoline (0.11 g, 35%); MS: 373 (M−100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:4](=[O:15])[CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[C:4](=[O:15])[CH:3]=1
Reactant: Cc1ccn(C2CCC(=O)CC2)c(=O)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ccn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c(=O)c1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-methyl-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[N:6][CH:7]=1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[CH:17]/[N:18]([CH3:20])[CH3:19])/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)/C(=C\N(C)C)c1cncc(Br)c1

Procedure:
5.1 g (20.8 mmol) of the compound from Example 8A in 7.1 ml (6.2 g, 41.8 mmol) of dimethylformamide diethyl acetal are heated at 100° C. for 16 h. After cooling, the mixture is concentrated under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[CH:12]=2.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[C@@H:31]1[CH2:33][O:32]1>CCO>[OH:32][C@H:31]([C:22]1[CH:23]=[CH:24][C:25]2[C:26](=[O:30])[O:27][CH2:28][C:29]=2[C:21]=1[CH3:20])[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([C:18]#[N:19])[CH:12]=3)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1ccc2cc(N3CCNCC3=O)cnc2c1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3cnc4cc(C#N)ccc4c3)C(=O)C2)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
A mixture of 3-(2-oxopiperazin-1-yl)quinoline-7-carbonitrile [I-4] (17 mg, 0.067 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (19 mg, 0.10 mmol) in EtOH (1.5 mL) in a 5 mL microwave tube was heated to 140° C. for 1 hour. LC showed formation of the title product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 443 [M+1]+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([N:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[CH:11]=1>CS(C)=O>[Cl:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([N:16]2[CH2:17][CH2:18][C:19]3([O:22][CH2:2]3)[CH2:20][CH2:21]2)[CH:11]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCN(c2cc(Cl)ncn2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cc(N2CCC3(CC2)CO3)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of trimethylsulfoxonium iodide (10.56 g) in dimethylsulfoxide (50 ml) was added 60% sodium hydride (1.84 g) in oil, and the mixture was stirred at room temperature for 1 hour. To the mixture was added, under ice-cooling, 1-(6-chloropyrimidine-4-yl)piperidin-4-one (8.50 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice-water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated, and the residue was crystallized from diethylether to give colorless crystals of 6-(6-chloropyrimidine-4-yl)-1-oxa-6-azaspiro[2,5]octane (5.67 g).
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[C:31]1([C@@H:37]([CH2:39][OH:40])[NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH3:41][C:42]1[S:46][C:45]([C:47](O)=[O:48])=[C:44]([NH:50][C:51]2[CH:56]=[CH:55][N:54]=[C:53]3[NH:57][CH:58]=[CH:59][C:52]=23)[CH:43]=1.N1C2=NC=CC(NC3C=CSC=3C(O)=O)=C2C=C1>>[OH:40][CH2:39][C@@H:37]([NH:38][C:47]([C:45]1[S:46][C:42]([CH3:41])=[CH:43][C:44]=1[NH:50][C:51]1[CH:56]=[CH:55][N:54]=[C:53]2[NH:57][CH:58]=[CH:59][C:52]=12)=[O:48])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(Nc2ccnc3[nH]ccc23)c(C(=O)O)s1
Reactant: N[C@H](CO)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Agent: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Product: Cc1cc(Nc2ccnc3[nH]ccc23)c(C(=O)N[C@H](CO)c2ccccc2)s1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (S)-2-phenylglycinol instead of 1-BOC-3-aminopyrrolidine and 5-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.26 (1H, s) 8.12 (1H, d, J=8.05 Hz) 8.01 (1H, d, J=5.42 Hz) 7.31-7.38 (2H, m) 7.25-7.31 (4H, m) 7.17-7.24 (1H, m) 6.79 (1H, d, J=5.47 Hz) 6.39 (1H, dd, J=3.54, 1.98 Hz) 5.07 (1H, td, J=7.71, 5.76 Hz) 4.90 (1H, t, J=5.76 Hz) 3.56-3.74 (2H, m, J=11.13, 11.13, 10.97, 5.76 Hz) 2.52 (3H, d, J=1.07 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.O=[C:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][CH:19]([NH:1][C:2]2[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7]3)[CH2:20][CH2:21]1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Product: Cc1cc(NC2CCOCC2)c2[nH]c(-c3ccccn3)cc2c1
Yield: 36 %

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole prepared in Step A of Example 1 and 4-oxo-tetrahydropyran were reacted according to the same procedure as Step B of Example 1 to give the title compound (25 mg, Yield 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:20])([F:19])[C:12]([OH:18])([CH3:17])[CH2:13][C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:14](=[O:15])[CH2:13][C:12]([OH:18])([CH3:17])[C:11]([F:20])([F:19])[F:10]
Reactant: CC(O)(CC(=O)O)C(F)(F)F
Reactant: Nc1ccc(Cl)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(O)(CC(=O)Nc1ccc(Cl)cc1N)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 4-chlorobenzene-1,2-diamine (1.32 g, 9.3 mmol), 4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (1.6 g, 9.3 mmol), HATU (4.24 g, 11.2 mmol), DIPEA (3.1 mL, 18.6 mmol) and DMF (25 mL) was stirred at room temperature overnight. The mixture was diluted with water (150 mL), and then extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), and then dried over Na2SO4, then filtered and concentrated. The residue was purified with flash column (30% EtOAc in PE to EtOAc) to give N-(2-amino-4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutanamide as brown oil (2.1 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]([O:31]C)[N:5]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>O1CCCC1CO>[CH3:1][C:2]1[NH:3][C:4](=[O:31])[N:5]([S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(OC)N(S(=O)(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: OCC1CCCO1
Product: CCOC(=O)C1=C(C)NC(=O)N(S(=O)(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A solution of 1, 2, 3, 6-tetrahydro-4-methyl-6-(3-nitrophenyl)-2-methoxy-1-(phenylsulfonyl)-5 -pyrimidinecarboxylic acid, ethyl ester (1.49 g, 3.24 mmol) in tetrahydrofuran-methanol (20 ml each) was treated with 5N hydrochloric acid (5.0 ml) and stirred at room temperature overnight. The reaction mixture was evaporated and partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride. Flash chromatography (acetone/hexanes (1:5)) and crystallization from dichloromethane/isopropyl ether gave the title compound as white crystals (589 mg), melting point 187°-188° C. 3 Analysis Calc'd. for C20H19N3O7S: C, 53.93; H, 4.30; N, 9.43; S, 7.20. Found: C, 53.71; H, 4.19; N, 9.27; S, 7.13.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]=1.FC(F)(F)C(O)=O>C(OCC)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1
Reactant: COc1ccccc1C1=NCCc2ccccc21
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1NCCc2ccccc21
Temperature: 5 °C
Yield: 81.6 %

Procedure:
Under an argon atmosphere, a 1.0 M borane-THF complex solution (110 mL) was added to a mixture of (1R,2S)-1-amino-2-indanol (8.17 g) and diethyl ether (200 mL) under stirring at an internal temperature of 5° C. or lower. The mixture was further stirred at room temperature for 1.5 hours. The mixture was cooled to an internal temperature of 4° C. 1-(2-methoxyphenyl)-3,4-dihydroisoquinoline (10 g) was gradually added to the mixture at an internal temperature of 5° C. or lower, followed by stirring at the same temperature for 30 minutes. The mixture was stirred at room temperature for 3 days. Trifluoroacetic acid (61 mL) was added to the reaction mixture to decompose an excess of reagent, further followed by heating under reflux for 3 hours. After cooling, diethyl ether was evaporated under reduced pressure and the mixture was heated under reflux for 10 minutes. The residue was diluted with chloroform and extracted with concentrated aqueous ammonia to be alkaline. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-EtOH-aqueous ammonia) to obtain 1-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (8.23 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=2[N:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(Cl)nc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(Cl)nc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-chloro-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C>[CH2:16]([O:15][C:13]([CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N+:20]([O-:22])=[O:21])=[C:2]([N:1]3[CH:25]=[CH:29][CH:28]=[CH:27]3)[CH:11]=2)[NH:6][C:7](=[O:19])[C:8]1=[O:18])=[O:14])[CH3:17]
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3)cc21
Temperature: 0 °C
Yield: 82.9 %

Procedure:
30 g (97 mmol) of 7-amino-1-(ethoxycarbonylmethyl)-6-nitro-2,3(1H,4H)-quinoxalinedione and 16.1 g (121.5 mmol) of 2,5-dimethoxytetrahydrofuran in 500 ml of acetic acid were heated at 80° C. for 1 h. The mixture was then poured into ice-water, and the precipitate was filtered off with suction to yield 28.8 g (83%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16](Cl)=[O:17].O>C(#N)C>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16](=[O:17])[NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10]
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: COCCOC(=O)Cl
Solvent: O
Solvent: CC#N
Product: COCCOC(=O)Nc1c(C)cc(Br)cc1C
Temperature: 130 °C
Yield: 82.1 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (2.00 g) and chloroformic acid 2-methoxyethyl ester (1.52 g) were dissolved in acetonitrile (25 mL) and heated to 130° C. for 15 minutes in a sealed microwave process vial. Water (25 mL) was added to the reaction mixture, and the product was collected by filtration and washed with water (25 mL) and heptane (25 mL) to furnish 2.48 g (82% yield) of the title compound as a white solid. LC-MS (m/z) 304 (MH+); tR=2.93, (UV, ELSD) 96%, 97%. 1H NMR (500 MHz, CDCl3): 2.36 (m, 6H), 3.40 (m, 3H), 3.60 (m, 2H), 4.35 (m, 2H), 6.55 (broad s, 1H), 7.45 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[C:12]([CH2:15][OH:16])[N:11]=[C:10]1[CH3:17]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[C:12]([CH:15]=[O:16])[N:11]=[C:10]1[CH3:17]
Reactant: Cc1nc(CO)c(C)n1-c1ccc(F)cc1F
Solvent: ClCCl
Product: Cc1nc(C=O)c(C)n1-c1ccc(F)cc1F

Procedure:
[1-(2,4-Difluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-yl]-methanol (0.38 g, 1.6 mmol) was dissolved in 35 ml dichloromethane. Mangan(IV)oxid (1.38 g, 16 mmol) was added, and the reaction mixture stirred at reflux for 2 hrs. The suspension was filtered through a dicalite speed plus pad and washed with dichloromethane. The solvents were evaporated, and the desired compound was obtained as a yellow oil (0.325 g, 86%), MS: m/e=237.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]=[C:10]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:22]=3)[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:23]([C:21]1[CH:22]=[C:17]([C:10]2[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[N:9]=2)[CH:18]=[N:19][CH:20]=1)#[CH:24]
Reactant: Cc1cccc(-c2nc(-c3cncc(C#C[Si](C)(C)C)c3)c3cc[nH]c3n2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cncc(-c2nc(-c3cccc(C)n3)nc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(6-methyl-pyridin-2-yl)-4-(5-trimethylsilanylethynyl-pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 216) (1 eq, 0.181 mmol, 70 mg) in THF (2 ml) is added TBAF (1 M in THF, 2 eq, 0.36 mmol, 0.36 ml). The resulting mixture is stirred for 10 min at r.t., then the solvent is removed in vacuo. Water is added, then the mixture is extracted with EtOAc. The organic layer is washed with sat. aqueous NaCl solution, dried with MgSO4, and concentrated under reduced pressure. The crude product is recrystallized from EtOAc giving the title compound; [M+H]+=312; 1H-NMR (400 MHz, CDCl3): δ 12.90 (s, 1H), 9.47 (d, 1H), 8.86 (d, 1H), 8.70-8.64 (m, 2H), 7.84 (t, 1H), 7.45 (m, 1H), 7.33 (d, 1H), 6.84 (d, 1H), 3.22 (s, 1H), 2.74 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([O:22]CC3C=CC=CC=3)[CH:19]=[CH:18][C:17]=2[N+:30]([O-])=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=2[NH2:30])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(OCc3ccccc3)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(O)ccc2N)c1
Yield: 98.7 %

Procedure:
5% carbon-palladium (3.2 g) was added to an ethyl acetate (300 ml) solution of tert-butyl[3-(5-benzyloxy-2-nitrophenoxy)benzyl]carbamate (10.5 g, 23.3 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure to give a brown oil of tert-butyl[3-(2-amino-5-hydroxyphenoxy)benzyl]carbamate (7.6 g, 98.8%).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:12][C:11]=1[CH3:29])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[N:32]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:39][CH:38]=3)[N:32]=2)=[CH:12][C:11]=1[CH3:29])([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNCc2ccc(C(F)(F)F)cc2)cc1C
Reactant: FC(F)(F)c1ccc(-c2cccc(Br)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 70 °C
Yield: 45.7 %

Procedure:
A mixture of ethyl 2-methyl-2-[2-methyl-4-({[4-(trifluoromethyl)benzyl]amino}methyl)phenoxy]propanoate (0.13 g, 0.318 mmol ), 2-bromo-6-[4-(trifluoromethyl) phenyl]pyridine (78.5 mg, 0.26 mmol), palladium (II) acetate (4.8 mg, 0.021 mmol), (R)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (19.8 mg, 0.032 mmol) and caesium carbonate (0.13 g, 0.397 mmol) in toluene (1.8 mL) were heated at 70° C. in a reactivial for 18 hours. After cooling to room temperature, the reaction mixture was filtered and the solvent removed in vacuo. Purification by SPE (Silica, 10 g) eluting with 99:1–19:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (75 mg).