Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([CH3:43])[O:42][CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([N:39]3[CH2:40][CH2:41][O:42][C:37]([C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)([CH3:43])[CH2:38]3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1(c2ccc(Cl)cc2)CNCCO1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate, 2-(4-chlorophenyl)-2-methylmorpholine and iPr2NEt (20.1 mg, 0.156 mmol) in DMF was heated at 100° C. for 10 hours. The mixture was evaporated to dryness and separated on CombiFlash, eluting with 0-70% EtOAc/Hex to give title compound. LCMS-ESI+: calc'd for C33H36Cl2N2O4S: 627.2, 629.2 (M+H+); found: 627.3, 629.3 (M+H+).
Reaction SMILES: C1(C[NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[CH:26]1([CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([CH2:32][CH2:33][S:34]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=2)(=[O:36])=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)CCC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Product: CC(C)(C)OC(=O)NCCCc1cccc(NS(=O)(=O)CCC2CCCCC2)c1

Procedure:
Sulfonation of aniline 17 by 2-cyclohexylethanesulfonyl chloride following the method used in Example 6 gives tert-butyl 3-(3-(2-cyclohexylethylsulfonamido)phenyl)propylcarbamate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:19]=1[C:20](O)=O>>[F:17][C:18]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:19]=1[C:20]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1cc(F)ccc1F
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cc(F)ccc2F)o1
Yield: 68 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,5-difluorobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 211 mg, 68%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)[CH:14]=[C:13]([CH3:26])[C:3]=1[O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[CH2:7]1.C(O)C.[H][H]>[Pt]=O.C(OCC)(=O)C>[NH2:23][C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[C:13]([CH3:26])[C:3]([O:4][CH2:5][CH:6]3[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[CH2:7]3)=[C:2]([CH3:1])[CH:16]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc(C)c1OCC1CCCN(C)C1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(-c2cccc(N)c2)cc(C)c1OCC1CCCN(C)C1

Procedure:
A mixture of 3-[2,6-dimethyl-4-(3-nitrophenyl)phenoxymethyl]-1-methylpiperdine (785 mg, 2.21 mmol), ethanol (10 mL), and ethyl acetate (5 mL) was hydrogenated overnight with platinum oxide (50 mg) at 1 atmosphere of hydrogen. The reaction was purged with nitrogen and filtered through Celite. The solids were washed with methanol and ethyl acetate. The filtrate and the washings were concentrated to give 3-[4-(3-aminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine as a yellow oil (735 mg, quantitative).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]=[CH:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13](O)[C:7]2=[N:6][CH:5]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:13]1[C:7]2[C:8](=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][N:6]=2)[N:10]=[CH:11][C:12]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cnc2nc(OCC)cnc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2nc(OCC)cnc2c1Cl
Temperature: 50 °C

Procedure:
Ethyl 3-ethoxy-8-hydroxypyrido[2,3-b]pyrazine-7-carboxylate (2.5 g) was added to a stirred solution of phosphorus oxychloride (50 ml) with stirring. The mixture was heated at 50° C. for 3 hours and then worked up as described in Example B1 to give ethyl 8-chloro-3-ethoxypyrido[2,3-b]pyrazine-7-carboxylate which was used directly.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([SH:22])[CH2:19][CH2:20][SH:21]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]3[S:22][CH2:18][CH2:19][CH2:20][S:21]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SCCCS
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Solvent: ClC(Cl)Cl
Product: c1cc(C2SCCCS2)ccc1OCCN1CCCCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
A 500 mL, 3-neck round bottom flask was charged with 4-[2-(1-piperdinyl)ethoxy]benzaldehyde (2.3 g, 10.0 mmol) and 1,3-propanedithiol (1.2 mL, 1.1 g, 10.2 mmol) in 250 mL of anhydrous chloroform under a nitrogen atmosphere. The solution was cooled to near 0° C. and dry HBr gas was slowly bubbled through the reaction mixture for 8 minutes. The mixture was allowed to warm to ambient temperature while stirring during 3.5 hr. The reaction mixture was then added to a large excess of 1N NaOH and ice and the chloroform layer was separated. The chloroform solution was washed with two 50 mL portions of 1N NaOH solution and two 25 mL portions of brine and dried over anhydrous sodium sulfate. After filtration and removal of the chloroform solvent, the residue was triturated with 1:1 hexane:ethyl ether to provide 2.19 g (68%) of a crystalline product which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f24) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:38])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:37])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:40])[CH3:39].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH3:37][C@:8]12[C@@:7]3([CH3:38])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:39])([CH3:40])[C:2](=[O:1])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:21]([C:24]([CH3:26])=[CH2:25])[CH2:22][CH2:23][C@:11]1([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:10][CH2:9]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-benzyl 9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (7.1 g, 12.98 mmol) in dichloromethane (100 mL) was added PCC (4.20 g, 19.48 mmol). After stirring for five minutes, the mixture turned a deep crimson color. The mixture was further stirred for 5.5 h. The mixture was filtered through a pad of celite and silica gel which was washed with dichloromethane and then with a 1:1 mixture of ethyl acetate:hexanes. The filtrate was concentrated under reduced pressure to give the title compound (6.92 g, 12.7 mmol, 98% yield) as a white foam. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.38-7.28 (m, 5H), 5.17-5.06 (m, 2H), 4.72 (d, J=1.83 Hz, 1H), 4.59 (s, 1H), 3.01 (td, J=10.99, 4.88 Hz, 1H), 2.51-2.43 (m, 1H), 2.42-2.34 (m, 1H), 2.28 (dt, J=12.59, 3.17 Hz, 1H), 2.21 (td, J=12.28, 3.51 Hz, 1H), 1.94-1.82 (m, 3H), 1.67 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 1.73-0.95 (m, 17H), 0.94 (s, 3H), 0.89 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.CN(C)C=O.S(Cl)([Cl:24])=O>>[Cl:24][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:15]=1
Reactant: O=c1[nH]c(-c2cccs2)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nc(-c2cccs2)nc2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 22.8 g of 2-(2-thienyl)-quinazolin-4(3H)-one in 200 ml of thionyl chloride was added in small quantities 7.3 g of dimethylformamide. The mixture was stirred for 2 hours, then poured into 2 liters of ice. The yellow solid was recrystallized three times from cyclohexane to give 16.7 g of 4-chloro-2-(2-thienyl)-quinazoline, m.p. 121.5°-123°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:27][CH3:28])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)OCC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: 2-(2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-propionic acid ethyl ester and benzyl chloroformate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH3:20][N:21]([CH3:23])[CH:22]=[CH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-5-nitro-2-phenoxy-pyridine (0.2 g, 0.86 mmol) and N,N-dimethylformamide dimethyl acetal (0.13 g, 1.1 mmol) in DMF (1 mL) was stirred at 130° C. for 1 hr, then cooled and concentrated to yield crude dimethyl-[2-(5-nitro-2-phenoxy-pyridin-4-yl)-vinyl]-amine as a syrup.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11](=O)[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([Cl:23])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(Cc3ccccc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(Cc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-benzyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[C:17]([CH3:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[CH3:10][C:11]1[C:17]([CH3:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:12]=1[NH:13][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([CH3:18])[C:11]=2[CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1c(N)ccc(O)c1C
Product: Cc1c(O)ccc(Nc2ncc(F)c(Nc3ccc(O)c(C)c3C)n2)c1C

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 2,3-dimethyl-4-hydroxyaniline gave N2,N4-bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 19.07 min.; purity: 99%; MS (m/e): 369 (MH+); 1H NMR (DMSO-d6): δ 9.21 (1H, s), 8.99 (1H, s), 8.63 (1H, s), 7.92 (1H, s), 7.84 (1H, d, J=3.6 Hz), 6.94 (1H, d, J=8.5 Hz), 6.85 (1H, d, J=8.5 Hz), 6.70 (1H, d, J=8.5 Hz), 6.58 (1H, d, J=8.5 Hz), 2.12 (3H, s), 2.06 (3H, s), 2.02 (3H, s), 1.94 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:20])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][CH:32]=O)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26].C([BH3-])#N.[Na+]>CO>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][CH2:32][N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:7](=[O:11])[O:8][CH2:9][C:10]=4[C:2]=3[CH3:1])[CH3:20])[CH2:15][CH2:16]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(CC=O)ccc1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CC(C)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-methyl-5-[1-(piperazin-1-yl)propan-2-yl]-2-benzofuran-1(3H)-one (25 mg, 0.080 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (17 mg, 0.097 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (7 mg, 0.113 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 434.3 [M+1]+. (0.17 μM)
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)CC(=O)N3)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Temperature: 78 °C
Yield: 75.1 %

Procedure:
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (0.735 g, 1.89 mmol) and ethyl formate (0.454 mL, 3.78 mmol) were dissolved in anhydrous ethanol (3.80 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (3.53 mL, 9.46 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (0.594 g, 1.42 mmol, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: Nc1cc(C(=O)O)ccc1I
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)c(N)c1

Procedure:
3-Amino-4-iodobenzoic acid (13.35 g, 50.8 mmol) was added to MeOH (150 mL) and SOCl2 (4.8 mL, 65.8 mmol, 1.3 equivalent) was added. The mixture was refluxed for 3 h and then volatiles were removed under reduced pressure. The residue was co-evaporated three times with MeOH and dried in vacuo (15.23 g).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([SH:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.Cl[C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>C1COCC1>[F:22][CH:2]([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([S:17][C:24]([O:26][CH3:27])=[O:25])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(S)c1CC(C)C
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Sc1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC(C)C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of 3.05 g (0.0089 mol) of product of example 1 and 0.094 g (0.01 mol) of methyl chloroformate in 25 mL dry THF was added 1.16 g (0.012 mol) of triethylamine dropwise at room temperature. After stirring for 30 min, the solvent was evaporated under reduced pressure. The residue was diluted with 100 mL of water and extracted with ether (3×50 mL). The combined organic layers were washed with water, dried (MgSO4) and evaporated. Purification of the residue by preparative HPLC (5% ethyl acetate-hexane) gave 2.75 g (77%) of product as a yellow oil: nD25 1.5830.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]1)[C:7]2=[O:25].[BrH:26]>>[BrH:26].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:7]2=[O:25]
Reactant: CCOC(=O)N1CCC(n2c(=O)c3cccc(Cl)c3n(C)c2=O)CC1
Agent: Br
Product: Cn1c(=O)n(C2CCNCC2)c(=O)c2cccc(Cl)c21

Procedure:
In 10 ml of 48% hydrobromic acid was dissolved 451.8 mg (1.24 mmol) of 8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound a) obtained in Reference Example 7, and the solution was heated under reflux for 1 hour. After the solvent was distilled off, ethanol was added to the residue, and the precipitated crystals were collected by filtration to give 119.5 mg of crude 8-chloro-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide. The crude product was dissolved in 10 ml of DMF, and 65 mg (0.29 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 122 mg (0.87 mmol) of potassium carbonate were added thereto, followed by heating at 120° C. for 2 hours. To the reaction mixture were added water and dilute hydrochloric acid for neutralization, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1). Ethyl acetate and ether were added to the product, and the precipitated crystals were collected by filtration and washed with ether to give 55.2 mg (yield: 8.9%) of Compound 15 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[OH-:10].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([OH:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)ncc1Cl
Temperature: 0 °C
Yield: 93.9 %

Procedure:
2,4,5-trichloropyrimidine (16.7 g, 91.0 mmol) was added to a tared, sealed flask and weighed. The oil was dissolved in 54 mL THF and cooled to 0° C. 1M aqueous NaOH solution (182 mL, 182 mmol) was added dropwise via an addition funnel, keeping the reaction at 0° C. This was allowed to warm to room temperature and concentrated to remove THF. Additional water was added to maintain dissolution. The pH was adjusted to 6 with a small quantity of HCl, and the aqueous was washed 3 times with ethyl acetate. The pH was then brought below 1 with more HCl, and extracted six times with ethyl acetate. This layer was washed with brine and dried over sodium sulfate. Product solution was filtered, concentrated, and dried on the high vacuum to give 14.1 g of 2,5-dichloropyrimidin-4-ol as an oil (96%).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1.CCN(CC)CC.[F:38]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C1COCC1>>[F:38][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C[C@H](C[C@H]1CC[C@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 39.2 %

Procedure:
A mixture of tert-butyl (S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (3 g, 7 mmol), Et3N (12 mL, 88 mmol), NEt3(HF)3 (4.71 mL, 29 mmol) and perfluorobutanesulfonyl fluoride (5.21 mL, 29 mmol) was stirred in THF (70 mL, 1 mmol/10 mL) at 50° C. until HPLC revealed complete conversion. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL), dried over MgSO4 and evaporated. The residue was then purified by prep HPLC to give tert-butyl (S)-1-(trans-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (1.16 g, 40%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.41 (d, 9H), 1.68 (m, 6H), 1.96 (m, 3H), 2.98 (d, 3H), 3.20 (m, 1H), 3.52 (m, 1H), 3.90 (m, 1H), 5.13 (d, 2H), 7.33 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=O)[CH3:25])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: COc1ccc(CC(C)=O)cc1
Product: COc1ccc(CC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-(4-methoxy-phenyl)-propan-2-one.