Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.C(O[CH:9]=[CH:10][C:11]([N:13]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])C>>[C:26]([N:23]1[CH2:24][CH2:25][CH:20]([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:11]2=[O:12])[CH2:21][CH2:22]1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC=CC(=O)N(c1ccccc1)C1CCN(C(=O)c2ccccc2)CC1
Agent: O=S(=O)(O)O
Product: O=C(c1ccccc1)N1CCC(n2c(=O)ccc3ccccc32)CC1
Temperature: 0 °C
Yield: 75.4 %

Procedure:
Conc. sulfuric acid (8 ml) is added to N-(β-ethoxyacryloyl)-N-(1-benzoyl-4-piperidinyl)aniline (0.8 g) and the mixture is reacted at 60° C. for 30 minutes. The reaction mixture is poured into ice-water and then extracted with dichloromethane. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1) to give 1-(1-benzoyl-4-piperidinyl)carbostyril (0.53 g).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[Cl:15])=[CH:4][C:3]=1[CH:18]=[O:19].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[Cl:15])=[CH:4][C:3]=1[CH2:18][OH:19]
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(Br)c(CO)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 4-(4-bromo-3-formylphenoxy)-3-chlorobenzonitrile (9.25 g, 27.4 mmol) in methanol (80 mL) was added sodium borohydride (522 mg, 13.7 mmol) portionwise at 0° C., and the mixture was stirred at room temperature for 1 h. The solvent was removed to about a half volume, 1 M HCl was added, and the mixture was poured into ethyl acetate/water. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (8:2 to 7:3 hexane/ethyl acetate) to give 4-(4-bromo-3-(hydroxymethyl)phenoxy)-3-chlorobenzonitrile (8.19 g, 3 steps, 85%).
Reaction SMILES: [CH3:1][O:2][P:3](Cl)([O:5][CH3:6])=[O:4].[NH2:8][C@H:9]([CH2:22][F:23])[C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[OH:11].C(N(CC)CC)C>ClCCl.C(#N)C.ClC(Cl)C>[F:23][CH2:22][C@@H:9]([NH:8][P:3](=[O:4])([O:5][CH3:6])[O:2][CH3:1])[C@H:10]([OH:11])[C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: COP(=O)(Cl)OC
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COP(=O)(N[C@H](CF)[C@H](O)c1ccc(S(C)(=O)=O)cc1)OC

Procedure:
Dimethylchlorophosphate (1.44 g; 10 mmol) dissolved in dichloromethane (4 ml) was slowly added dropwise to a mixture cooled to 0° C. of (1R,2 S)-2-amino-3-fluoro-1-(4-methylsulfonylphenyl)-1-propanol (2.47 g; 10 mmol) in acetonitrile (15 ml) and dichloroethane (15 ml) containing triethylamine (1.39 ml; 10 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CC([O-])(C)C.[K+].[C:18]([O:22][C:23](=O)[O:24]C(C)(C)C)([CH3:21])([CH3:20])[CH3:19].Cl>CN(C=O)C.O>[C:18]([O:22][C:23]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([F:11])[CH:9]=2)[CH:5]=[CH:6]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Fc1cc2[nH]ccc2cc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(Br)c(F)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of 2.1 g (9.81 mmol) 5-Bromo-6-fluoro-indole in 35 ml of DMF were added 1.54 g (13.76 mmol) KOtBu and 3.0 g (13.76 mmol) Di-tert.butylcarbonate, and the solution was stirred for 1 hr at room temperature and 30 min at 60° C. The mixture was poured into water, acidified with 2M aqueous HCl and extracted with Et2O. Drying of the organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with hexane/EtOAc 49:1 gave 2.6 g (84%) 5-Bromo-6-fluoro-indole-1-carboxylic acid tert-butyl ester as a colorless liquid, MS: 313 (M, 1Br).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:4][CH:5]=2)[C:12](=[O:26])[CH:13]=1
Reactant: C1CCNC1
Reactant: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 80 mg (0.19 mmol) 1-[2-(4-Bromomethyl-phenyl)-ethyl]-4-(2-fluoro-benzyloxy)-1H-pyridin-2-one (example 9.1b) in 1.5 mL DMF is added at RT 63 μL (0.77 mmol) pyrrolidine. The reaction mixture is stirred overnight at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
0.43 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (produced in Intermediate Production Example 1) was dissolved in 2.0 ml of N,N-dimethylformamide, and to this was added 0.15 g of anhydrous potassium carbonate, and 0.17 g of methyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 3 hours at 70° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residues was subjected to silica gel column chromatography to obtain 0.39 g of methyl 2-[4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 1-1 of the present invention].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1C=CC(S(O[CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[C:13]([O:17][CH2:29][CH2:30][NH:31][C:32](=[O:33])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:14]=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(O)n2)c1=O
Reactant: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc(Nc2cccc(OCCNC(=O)OC(C)(C)C)n2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 15.6 %

Procedure:
A mixture of compound 101a (7.0 g, 23.75 mmol), 2-(tert-butoxycarbonylamino)ethyl 4-methylbenzenesulfonate (3.0 g, 9.5 mmol) and Cs2CO3 (3.7 g, 11.4 mmol) in DMF (40 mL) was stirred at 100° C. for 4 h. The reaction mixture was concentrated. The residue was treated with EA and filtered. The filtrate was washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give Tert-butyl 2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethylcarbamate 101b (650 mg, 15% for two steps) as a yellow solid. A mixture of 101b (700 mg, 1.6 mmol) in HCl (5 mL, 4M in 1,4-dioxane, 20 mmol) was stirred at rt overnight. The reaction mixture was concentrated to give 103a (550 mg, 83%) as yellow solid. MS-ESI: [M+H]+ 341.0
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1.O>ClCCl>[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH:1][CH2:2][C:3]2[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]3[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]3=[N:7][C:8]=2[CH2:9][CH3:10])=[O:45])=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccc(CCCCOCCCCBr)cc1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCOCCCCBr)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.3 %

Procedure:
A solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (300 mg, 1 mmol, e.g. which can be as prepared in Intermediate 7) and triethylamine (0.34 ml, 2.5 mmol, 2.5 equivalents) in dichloromethane (20 ml) was stirred and cooled in an ice/water bath under an atmosphere of nitrogen. 4-{4-[(4-Bromobutyl)oxy]butyl}benzoyl chloride (520 mg, 1.5 mmol, 1.5 equivalents, e.g. which can be as prepared in Intermediate 26) was added portion-wise over 2 minutes, and the mixture was stirred at 0° C. for 5 minutes and then at room temperature for 3 hours. Iced water was added to the reaction mixture and the organic phase was separated and collected through a hydrophobic frit. The aqueous phase was extracted with dichloromethane (10 ml), and the organic layers were combined and evaporated to dryness to give a brown oil. The residue was purified by flash chromatography (100 g silica cartridge, FlashMaster II), eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 40 minutes. The fractions containing the product were combined and evaporated to dryness to give the title compound as a glass (0.26 g). LCMS showed MH+=614/616 (Bromine isotope pattern); TRET=3.06 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]1([C:23](=O)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:23]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:24]([C:25]#[N:26])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N#CCC(=O)C1CCCCC1
Product: N#Cc1c(C2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chlorophenyl)(phenyl)methanone and 3-cyclohexyl-3-oxo-propionitrile. Colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([Cl:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[C:22]([Cl:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:53]=[C:54]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:55]=[N:56][CH:57]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:61][S:58]([C:54]1[CH:53]=[C:52]([C:2]2[CH:11]=[C:10]3[C:5]([N:6]=[CH:7][C:8]([N:12]4[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:16][CH2:17]4)=[N:9]3)=[CH:4][CH:3]=2)[CH:57]=[N:56][CH:55]=1)(=[O:60])=[O:59]
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)NCCN1CCN(c2cnc3ccc(Br)cc3n2)CC1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCN1CCN(c2cnc3ccc(-c4cncc(S(N)(=O)=O)c4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A slurry of 1,1-dimethylethyl {2-[4-(7-bromo-2-quinoxalinyl)-1-piperazinyl]ethyl}carbamate (0.96 mmol), bis(pinacolato)diboron (1.06 mmol), potassium acetate (3.84 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.07 mmol) in 1,4-dioxane (5 ml) was heated at 100° C. After the reaction stirred for 1 hour, 5-bromo-3-pyridinesulfonamide (0.96 mmol) and 2M potassium carbonate (aq) (4 ml) was added and the reaction mixture stirred for 18 hours. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (10% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (20 mg, 7%) as a light yellow solid. MS(ES)+ m/e 514.2 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Li+].[H-].[Cl:13][CH:14]=[C:15]1[CH:21]=[CH:20][C:19]2[CH:22]=[C:23]([C:26](OC)=[O:27])[CH:24]=[CH:25][C:18]=2[O:17][CH2:16]1>ClCCl>[Cl:13][CH:14]=[C:15]1[CH:21]=[CH:20][C:19]2[CH:22]=[C:23]([CH2:26][OH:27])[CH:24]=[CH:25][C:18]=2[O:17][CH2:16]1
Reactant: COC(=O)c1ccc2c(c1)C=CC(=CCl)CO2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: OCc1ccc2c(c1)C=CC(=CCl)CO2
Reaction time: 1 h
Yield: 108.9 %

Procedure:
2.72 ml (2.72 mmol) of a lithium diisobutylaluminum hydride solution are added at a temperature of −78° C. to 217 mg (0.87 mmol) of methyl 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 32, in solution in 10 ml of dichloromethane. The solution is stirred at this temperature for 1 hour. A conventional treatment makes it possible to isolate 211 mg (100%) of [3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-yl]methanol in the form of a white solid comprising two Z/E isomers as a mixture in a 90/10 ratio; 1H NMR (C6D6): 6.98 (d, J=8.2 Hz, 1H), 6.97 (m, 1H), 6.90 (dd, J=8.2 Hz and 2.2 Hz, 1H), 6.07 (d, J=11.8 Hz, 1H), 5.86 (d, J=11.8 Hz, 1H), 5.74 (s, 1H), 4.68 (s, 2H), 4.28 (4.1) (s, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[N:11]=[C:10]([N:3]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccccc1
Product: CN(c1ccccc1)c1nc(N(C)c2ccccc2)c2ccccc2n1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methylaniline (40 μL, 0.401 mmol) by a procedure similar to Example 1b and was isolated as white powder (33 mg, 66%). 1H NMR (CDCl3): 7.54 (dd, J=8.2 and 0.6 Hz, 1H), 7.45 (dd, J=8.4 and 1. Hz, 1H), 7.44-7.29 (m, 6H), 7.21-7.10 (m, 4H), 6.86 (dd, J=8.4 and 0.9 Hz, 1H), 6.67 (ddd, J=8.4, 7.2 and 1.1 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][C:32](=[O:36])[CH2:31]2)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:32](=[O:36])[CH2:31]2)=[CH:37][CH:38]=1
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 33.5 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.6 g, 4.4 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (0.96 g, 4.3 mmol) were reacted according to Example 2 (step f) to provide the title compound (730 mg, 33%) as a yellow powder: ESI MS m/z 507 [M+H]+.
Reaction SMILES: ClC([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)=O.[CH2:32]([NH2:35])[CH2:33][NH2:34].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:21][CH:19]([CH2:18][CH2:17][CH2:16][C@H:15]([C@@H:14]1[C@:23]2([CH3:31])[C@H:11]([C@H:10]3[C@H:26]([CH2:25][CH2:24]2)[C@:27]2([CH3:30])[C:7]([CH2:6][C@H:5]([CH2:29][CH2:28]2)[OH:4])=[CH:8][CH2:9]3)[CH2:12][CH2:13]1)[CH3:22])[CH3:20].[CH2:32]([NH2:35])[CH2:33][NH2:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
Solid cholesterol chloroformate (10 mmol) was dissolved in 100 mL of dichloromethane (DCM). In a separate flask 0.5 mol ethylenediamine was diluted with 200 mL of DCM and 20 mmol diisopropylethylamine. While stirring, the cholesterol chloroformate solution was drop-wise added to the ethylenediamine solution over a 30 minute period at room temperature (R.T.). Following an overnight R.T. stir, organic solvent was roto-evaporated away using medium vacuum until a minimal sample volume remained. Approximately 400 mL of acetonitrile was added to precipitate the crude product. The solid was then collected by filtration onto a Whatman #5 filter apparatus, rinsed several times with acetonitrile and then air-dried. The crude solid was dissolved in a minimal volume of chloroform and chromatographically purified using a silica column. The purified product presented a single TLC spot (4:1 chloroform/methanol), and a single peak (parent ion M+H=474) was identified by positive mode electrospray.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].N1C=CC=CC=1>CCOC(C)=O>[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
EtSO2Cl (21.5 mL, 0.22 mol) was added drop wise to a mixture of 4-fluoro-3-nitroaniline (29.6 g, 0.19 mol) and pyridine (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (1 L). The resulting solution was washed with HCl 2N (4×200 mL), NaHCO3 saturated solution (4×200 mL) and water (4×200 mL). The organic phase was dried over anhydrous Na2SO4 and the solvent was removed to provide the title product as beige solid (46.3 g)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]=[O:36])=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([CH3:38])([CH3:37])[CH2:34][CH:35]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[OH:36])=[CH:31][CH:32]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(CC=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
A stirred solution of 5.0 mL (0.036 mole) of diisopropylamine in 100 mL of tetrahydrofuran was cooled to 0° C., and 14.3 mL (0.036 mole) of n-butyllithium (2.5M in hexanes) was added dropwise. Upon completion of addition, 9.6 grams (0.036 mole) of tributyltin hydride was added dropwise during a 15 minute period. The reaction mixture was then stirred at 0° C. for 15 minutes. After this time the reaction mixture was cooled to -78° C., and a solution of 7.0 grams (0.036 mole) of 3-(4-chlorophenyl)-3-methylbutyraldehyde in 10 mL of tetrahydrofuran was added dropwise, while maintaining the reaction mixture temperature below -70° C. The complete addition required about 20 minutes. After this time the reaction mixture was stirred at below -70° C. for ten minutes. The reaction was then quenched by the dropwise addition of about 300 mL of aqueous dilute ammonium chloride solution to the cold reaction mixture. The complete addition required about 10 minutes. The cooling bath was removed, and the reaction mixture was extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, at a temperature of less than 30° C., yielding 17.4 grams of 3-(4-chlorophenyl)-3-methyl-1-tributylstannylbutanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C@@H:8]([C:20]([O:22]C)=[O:21])[NH:9][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@H:8]([C:20]([OH:22])=[O:21])[NH:9][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccccc2)C(=O)O)cc1
Yield: 61.4 %

Procedure:
The same procedures as in Example 90 were carried out from the compound obtained in Example 41 (3.4 g), 1 mol/L of an aqueous sodium hydroxide solution (19 mL), and methanol (150 mL), to give the captioned compound (2.0 g, 62%) as crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[CH:5][C:6]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=1[C:8]([NH:10][C:11]1([C:20]([OH:22])=[O:21])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:9]>CCO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=1[C:8]([NH:10][C:11]1([C:20]([OH:22])=[O:21])[CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19]1)=[O:9]
Reactant: COCC=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Agent: [Pd]
Solvent: CCO
Product: COCCCc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Yield: 64 %

Procedure:
To a solution of 2-[2-(3-methoxy-propenyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid (229) (120 mg, 0.34 mmol) in absolute EtOH (15 mL) is added the catalyst, Pd—C (5 wt. % Pd, 93 mg, 4.4% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 55 psi, 50° C., overnight. The catalyst is removed by the filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined organic solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (222) as white solid (80 mg, 49%).