Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])O.[Na+].C1COCC1.Cl[C:46]([O:48][C:49]1[CH:58]=[CH:57][C:52]([C:53]([O:55]C)=[O:54])=[CH:51][CH:50]=1)=[O:47]>O>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:46]([O:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([OH:55])=[O:54])=[CH:51][CH:50]=2)=[O:47])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a mixture of 192 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 157 mg of sodium hydrogen carbonate were added 3 mL of THF and 1.5 mL of water, followed by addition of 133 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). It was stirred at room temperature for 1 hour, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to 327 mg of the obtained residue were added 4 mL of THF, 2 mL of methanol, and 2.5 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. The reaction mixture was neutralized by addition of 2.6 mL of 1 M hydrochloric acid, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 228 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a colorless foamy substance. ESI+: 627
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.[NH2:19][C:20]1(OCC)[CH:25]=[CH:24][C:23](O)=[CH:22][CH2:21]1.C(N(C(C)C)CC)(C)C.CN1[C:44](=[O:45])[CH2:43]CC1>C(OCC)(=O)C.O>[OH:45][CH2:44][CH2:43][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=2)=[CH:25][CH:24]=1
Reactant: CN1CCCC1=O
Reactant: Cc1cccc(Nc2nc(Cl)ncc2C(N)=O)c1
Reactant: CCOC1(N)C=CC(O)=CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Nc2nc(Nc3ccc(CCO)cc3)ncc2C(N)=O)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 2.0 g of 2-chloro-4-{(3-methylphenyl)amino}pyrimidine-5-carboxamide, 1.25 g of 4-aminophenetyl alcohol, 1.99 ml of diisopropylethylamine and 10 ml of NMP was stirred overnight at 110° C. The reaction mixture was cooled down to room temperature and mixed with water and ethyl acetate, and the thus precipitated solid was collected by filtration and recrystallized (methanol) to obtain 560 mg of 2-{[4-(2-hydroxyethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH3:15][CH:16]([NH2:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:23][CH:16]([CH3:15])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: CC(C)CCCC(C)N
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Product: CC(C)CCCC(C)NC1=NS(=O)(=O)c2cc(Cl)ccc2N1

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (300 mg; 1.19 mmol) and 1,5-dimethylhexylamine (1 g; 7.73 mmol) and with the use of same procedure as in example 21 260 mg (63.5%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.50 (s, 1H, NH), 7.68 (d, 1H, H-8), 7.63 (dd, 1H, H-5), 7.25 (d, 1H, H-7), 7.1 (br, 1H, NH), 3.85 (q, 1H, CH), 1.5 (m, 4H ), 1.35 (m, 3H ), 1.15 (d, 3H, CH3), 0.85 (d, 6H, 2×CH3).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C.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>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccccc1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(/C=C/c3ccccc3)c12
Temperature: 75 °C

Procedure:
A solution of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg, 0.159 mmol), styrene (0.022 mL, 0.191 mmol) and triethylamine (0.044 mL, 0.318 mmol) in DMF (3.0 mL) was degassed three times, charged with tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0159 mmol) degassed twice more and then heated at 75° C. for 16 h. The reaction mixture was then concentrated in vacuo dissolved in MeOH/CH3CN (1:1)(4 mL) and was filtered through a 0.45 μM fritted autovial prior to purification via mass directed preparative HPLC which afforded the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 1.87-1.99 (m, 1H), 2.02-2.17 (m, 1H), 2.37-2.47 (m, 4H), 3.18 (s, 2H), 3.83-3.94 (m, 1H), 6.94 (d, J=4.9 Hz, 1H), 7.25 (t, J=7.33 Hz, 1H), 7.32-7.40 (m, 3H), 7.45 (d, J=15.5 Hz, 1H), 7.63 (d, J=15.45 Hz, 1H), 7.73 (d, J=7.46 Hz, 2H); MS (ES+): m/z 291.15 [MH30 ].
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:20]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=3)[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)Cc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
120 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propanal (80 mg, 0.312 mmol), 1-phenylpiperazine (0.047 mL, 0.312 mmol), DIPEA (0.081 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: O.[C:2]([O-:5])([O-])=O.[Ca+2].[Br:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1CBr>O1CCOCC1>[Br:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:2][OH:5]
Reactant: BrCc1ccc2ccccc2c1Br
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc2ccccc2c1Br
Yield: 84.3 %

Procedure:
Water (100 ml) and CaCO3 (18 g, 180 mmole) were added to a solution of 13 in dioxane (100 ml) and the mixture was refluxed for 10 hr. The solution was cooled and the dioxane was removed under reduced pressure and the mixture was acidified with 1N HCl and extracted with methylene chloride. The combined methylene chloride fractions were washed with saturated solution of NaHCO3, H2O, brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a white solid which when crystallized from hexane afforded 7 g of 24 (84.3%). A single component was detected by TLC (100% hexane, Rf, 0; hexane/ethyl acetate 80:20, Rf, 0.5); NMR (CDCl3) d 2.1 (m, 1H, H--O), d 5.0 (s, 2H, CH2 --OH), d 7.4-8.4 (m, 6H, naphthyl); MS (HRFAB) calcd for C11H9BrO (M+Li)+ 243.0003 found 243.0003.
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:22][C:23]([CH3:30])([C:27](O)=[O:28])[C:24]([OH:26])=[O:25].CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[C:59]([N:78]1[CH:82]=[C:81]([CH2:83][CH2:84][CH2:85][NH2:86])[N:80]=[CH:79]1)([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl.CN(C=O)C.C(Cl)Cl.CN(C=O)C>[CH3:22][C:23]([CH3:30])([C:27]([NH:86][CH2:85][CH2:84][CH2:83][C:81]1[N:80]=[CH:79][N:78]([C:59]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:82]=1)=[O:28])[C:24]([OH:26])=[O:25]
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C(=O)O)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C(=O)O)C(=O)NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:DMF 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in DMF for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and DMF (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtered and 3-(1-Trityl-1H-imidazol-4-yl)-propyl amine (1.8 eq; 5.40 mmol; 1.84 g), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and DMF (10 mL) was added. The resin was shaken for 2 days. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). 2,2,2-Trifluoroethanol/dichlormethan 1:1 (20 mL) was added to the resin and it was shaked for 2 hrs. The resin was washed with 2,2,2-Trifluoroethanol/dichlormethan 1:1 (10 mL) and the combined filtrates were collected and concentrated in vacuo to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([F:36])([F:38])[F:37]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 214, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 4-fluoro-3-(trifluoromethyl)benzaldehyde in the presence of cesium carbonate to give the title compound as an off-white solid. MS (m/e)=548.1 [M+H+].
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH:22]([OH:24])[CH3:23])[CH:21]=1)[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:17]=[C:16]2[C:33]#[N:34].[Cl:35][C:36]([Cl:40])([Cl:39])[C:37]#[N:38]>C1COCC1>[Cl:35][C:36]([Cl:40])([Cl:39])[C:37](=[NH:38])[O:24][CH:22]([C:20]1[CH:21]=[C:13]([Cl:12])[CH:14]=[C:15]2[C:19]=1[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH:17]=[C:16]2[C:33]#[N:34])[CH3:23]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2c(C#N)cn(COCC[Si](C)(C)C)c12
Reaction time: 1 h
Yield: 73.4 %

Procedure:
DBU (0.020 mL, 0.130 mmol) was added to a solution of (±)-5-chloro-7-(1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-3-carbonitrile (456 mg, 1.299 mmol) and Trichloroacetonitrile (0.391 mL, 3.90 mmol) in THF (10 mL) and the reaction was stirred for one hour. The solvent was evaporated and the reaction was purified by chromatography on SiO2 with 10:89:1 ethyl acetate/hexanes/triethylamine to give (±)-1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (472 mg, 0.953 mmol, 73.3% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J=2.0 Hz, 1H), 6.60 (q, J=6.3 Hz, 1H), 6.27 (d, J=11.3 Hz, 1H), 5.25 (d, J=11.3 Hz, 1H), 3.48 (m, 2H), 1.72 (d, J=6.3 Hz, 3H), 0.80-1.05 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH:40]([OH:42])[CH3:41]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH:40]([OH:42])[CH3:41])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: CC(O)CCN
Product: CC(O)CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-2-butanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (d, J=6.32 Hz, 3 H), 1.37-1.87 (m, 10 H), 2.36-2.45 (m, 2 H), 3.32-3.48 (m, 5 H), 3.63-3.77 (m, 2 H), 4.12-4.23 (m, 4 H), 4.62 (br. s., 1 H), 7.14 (ddd, J=9.05, 6.63, 2.21 Hz, 2 H), 7.37-7.44 (m, 2 H), 7.99 (d, J=1.05 Hz, 1 H), 8.56 (d, J=1.26 Hz, 1 H), 10.35 (t, J=5.69 Hz, 1 H), 17.26 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].OS(O)(=O)=O.[BrH:16].CC(N=NC(C#N)(C)C)(C#N)C.OO>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([C:5]([Cl:8])=[CH:6][CH:7]=1)[CH2:9][Br:16]
Reactant: Br
Reactant: Cc1c(Cl)ccc(Cl)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OO
Solvent: Clc1ccccc1
Product: Cc1c(Cl)ccc(Cl)c1CBr
Temperature: 70 °C
Reaction time: 5 h

Procedure:
170.1 g (0.97 mol) of 3,6-dichloro-1,2-xylene are initially charged in 1180 ml of chlorobenzene, and 4.9 g of conc. H2SO4 and 203.1 g (1.18 mol) of 47% strength hydrobromic acid are added. The mixture is heated to 70° C., and 0.9 g of AIBN are added. Over a period of 5 h, 353.7 g (1.04 mol) of a 10% strength solution of hydrogen peroxide are added at 70-75° C., the mixture is stirred at 70-75° C. for 30 min, washed twice with 400 ml of water and once with 400 ml of saturated sodium bicarbonate solution, and the chlorobenzene is then distilled off.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH2:29].C(N(C(C)C)CC)(C)C>ClCCl.CCOCC>[CH3:25][O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH:29][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc(CBr)cc1-c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CBr)cc1-c1ccccc1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution in dichloromethane (25 mL) of 4-bromomethyl-2-phenylbenzoic acid (2.16 g, 7.42 mmol), prepared as in Example 234B, was added oxalyl chloride (0.84 mL, 965 mmol) and 2 drops on DMF and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (15 mL) and then was added to a solution in dichloromethane (15 mL) of methionine methyl ester hydrochloride (1.78 g, 8.90 mmol) and diisopropylethylamine (3.10 g, 17.81 mmol) (prepared at −10° C.) dropwise. The reaction mixture was stirred for 30 minutes and then was poured into ether and extracted with water, aqueous 3N HCl (2×) and brine, dried, filtered and concentrated in vacuo. Chromatography on silica gel (5% ethyl acetate-chloroforn) to give (4-bromomethyl-2-phenylbenzoyl)methionine methyl ester (2.42 g, 75%).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33]O)[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1.CCN(CC)CC.[CH2:46]([CH2:48][NH2:49])[OH:47]>C(Cl)Cl.CO>[F:38][C:7]([F:6])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][NH:49][CH2:48][CH2:46][OH:47])[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cc2c(F)c(Oc3ccnc(CO)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: NCCO
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(F)c(Oc3ccnc(CNCCO)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.046 mL, 0.586 mmol) is added to a solution of 4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (180 mg, 0.391 mmol) and Et3N (0.109 mL, 0.782 mmol) in CH2Cl2 (5 mL) at 0° C. After 10 min, ethanolamine (0.236 mL, 3.91 mmol) is added and the resulting mixture is warmed to and stirred at 23° C. for 4 h. MeOH (2 mL) is added and the reaction is stirred for another 15 h. The reaction mixture is partitioned between EtOAc (40 mL) and water (40 mL). The aqueous layer is extracted with EtOAc (2×40 mL). The combined organic layers are washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-10 MeOH/CH2Cl2) to give 4-fluoro-5-{2-[(2-hydroxy-ethylamino)-methyl]-pyrimidin-4-yloxy}-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 504.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.60 (d, J=5.81 Hz, 1H) 8.07 (s, 1H) 7.86 (s, 1H) 7.57-7.62 (m, 1H) 7.46-7.51 (m, 2H) 7.09 (dd, J=8.84, 7.33 Hz, 1H) 6.98 (d, J=5.81 Hz, 1H) 6.54 (s, 1H) 3.82 (s, 2H) 3.55-3.58 (m, 2H) 2.65-2.71 (m, 2H) 2.62 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[N:21]([O-])=O.[Na+].[OH-].[Na+].C(O)(=O)C>O.Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:2]2[N:1]=[N:21][N:6]([CH2:7][CH:8]([CH3:15])[CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[C:4](=[O:5])[C:3]=2[CH:16]=1
Reactant: CC(CNC(=O)c1cc(Cl)ccc1N)Cn1ccnc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(Cn1ccnc1)Cn1nnc2ccc(Cl)cc2c1=O

Procedure:
A solution of 5.86 g of 2-amino-5-chloro-N-[3-(1H-imidazol-1-yl)-2-methylpropyl]benzamide in 30 ml of water and 8.3 ml of concentrated hydrochloric acid was cooled in an ice bath and a solution of 1.42 g of sodium nitrite in 10 ml of water was added dropwise. The mixture was stirred, treated for 50 minutes with 10 ml of 10N sodium hydroxide, stirred for 50 minutes and acetic acid was added until a pH of 6-7 was reached. The product was extracted into methylene chloride and the organic layer was washed with water, dried over magnesium sulfate and concentrated. Treatment with ethyl ether resulted in crystals of the desired product, mp 100°-102° C. A sample was converted to the hydrochloride salt, mp 185°-188° C.
Reaction SMILES: [C:1]([N:8]([CH3:19])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CC(C)=O>[C:1]([N:8]([CH3:19])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:14][CH:13]=1)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CN(CC(=O)c1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 4-[2-(BOC-methylamino)acetyl]phenol (5.04 g, 19.0 mmol) and K2CO3 (2.63 g, 19.0 mmol) in acetone (100 mL) was stirred at reflux under argon for 1 h. The mixture was cooled to RT and benzyl bromoacetate (5.23 g, 22.8 mmol) was added. The reaction was heated at reflux for 18 h, then was cooled and filtered. The filter cake was washed with acetone, and the filtrate was concentrated on the rotavap. The residue was dissolved in CH2Cl2 (300 mL) and washed sequentially with H2O (50 mL) and brine (50 mL). Drying (Na2SO4), concentration, and flash chromatography (silica gel, 1:3 EtOAc/hexanes) yielded the title compound (7.28 g, 93%): 1H NMR (250 MHz, CDCl3) δ 6.85-7.95 (m, 9 H), 5.23 (s, 2H), 4.71 (s, 2H), 4.55 (d, 2H), 2.95 (d, 3H), 1.45 (d, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][N:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc2c(Cl)cnnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cnnc2cc(CBr)ccc12
Temperature: 80 °C
Yield: 35.6 %

Procedure:
A solution of 4-chloro-7-methylcinnoline (0.6 g, 3.37 mmol) in carbon tetrachloride (30 mL) is treated with N-bromosuccinimide (0.64 g, 3.4 mmol) and a catalytic amount of 70% benzoyl peroxide (0.22 g, 0.63 mmol). The solution is heated to 80° C. overnight, then filtered. The filtrate is concentrated in vacuo and the resulting residue is chromatographed (20% ethyl acetate/methyl chloride) to give the title compound (0.3 g, 1.2 mmol) and some unreacted starting material (0.1 g, 0.56 mmol). MS m/z: [M+H]+=257; 1H NMR (CDCl3, 300 MHz) δ9.35 (s, 1H), 8.55 (s, 1H), 8.2 (d, 1H), 8.85 (d, 1H), 4.75 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:13](N)[CH2:14][NH2:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:10]2[NH:15][CH2:14][CH2:13][N:11]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: NCCN
Reactant: COc1cccc(C(C)C#N)c1
Product: COc1cccc(C(C)C2=NCCN2)c1

Procedure:
rac-2-[1-(3-Methoxy-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(3-methoxyphenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): yellow oil; MS (ISP): 205.3 ((M+H)+.).
Reaction SMILES: BrC(Br)C[C:4]1[C:9]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:21].[OH2:25]>>[C:13]1([C:11]2[O:25][C:7]3[C:8](=[C:9]([CH:10]=[O:21])[CH:4]=[CH:5][CH:6]=3)[N:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrC(Br)Cc1cccc2[nH]c(-c3ccccc3)cc12
Reactant: O
Reactant: O=S(=O)(O)O
Product: O=Cc1cccc2oc(-c3ccccc3)nc12

Procedure:
5.5 g (14.9 mmol) of the compound from Example XII were stirred at 100° C. with 30 ml of concentrated sulphuric acid for 1 h, the mixture was poured into water, and the precipitate was filtered off with suction and dried. Yield: 3.3 g (100% of theory) M.p.: 116° C.