Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(O)(=O)CCCCCCCCCCCCCCCCC.[NH2:33]CCS(O)(=O)=O.N([O-])=O.[Na+].N([O-])=O>O>[C:1]1([S:7]([N:10]=[N+:11]=[N-:33])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCS(=O)(=O)O
Reactant: NNS(=O)(=O)c1ccccc1
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
25 g of benzenesulphonohydrazide, 200 ml of water, 20 ml of 10N hydrochloric acid and 1.25 g of a condensation product of stearic acid with taurine are stirred for 30 minutes. 60 g of ice are added, and 34 ml of an aqueous sodium nitrite solution containing 30 g of sodium nitrite in 100 ml of solution are then added dropwise in the course of about 30 minutes. The batch is stirred for 30 minutes, an excess of nitrite being maintained. The nitrite excess is then destroyed with a small amount of sulphamic acid, and excess acid is neutralised with about 5 ml of 10N sodium hydroxide solution. An emulsion of benzenesulphonyl azide is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:19][C:20]([CH3:24])([C:22]#[CH:23])[OH:21]>>[OH:21][C:20]([CH3:24])([CH3:19])[C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1CCO2

Procedure:
9-Bromo-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide (0.15 g) was reacted with dimethyl ethynyl carbinol similar to as described in Procedure E to afford 56.9 mg of 9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide following reverse phase hplc purification. MS (Q1) 329 (M)+. 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=2.1 Hz, 1H), 8.39 (s, 1H), 7.84 (s, 1H), 7.27 (dd, J=8.3, 2.1 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 5.40 (s, 1H), 4.34 (t, J=4.9 Hz, 2H), 3.41 (t, J=4.9 Hz, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C@H:31]5[CH2:35][CH2:34][NH:33][CH2:32]5)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:46].[C:47]1(=O)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH:47]1([N:33]2[CH2:34][CH2:35][C@H:31]([O:30][C:27]3[CH:26]=[CH:25][C:24]([CH:23]4[CH2:22][CH2:21][N:20]([C:36]([O:38][CH2:39][C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)=[O:37])[CH2:19][CH:18]4[O:17][CH2:16][C:13]4[CH:14]=[CH:15][C:10]5[O:9][CH2:8][C:7](=[O:46])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=5[CH:12]=4)=[CH:29][CH:28]=3)[CH2:32]2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C1CCCCC1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O[C@H]4CCNC4)cc3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O[C@H]4CCN(C5CCCCC5)C4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.374 g of benzyl 3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(pyrrolidin-3(S)-yloxy)phenyl]piperidine-1-carboxylate is admixed under argon with 0.038 ml of acetic acid and 0.078 ml of cyclohexanone. 0.199 g of sodium triacetoxyborohydride is added in portions at room temperature to this reaction solution and the reaction mixture is subsequently stirred at room temperature over one hour. The reaction mixture is concentrated by evaporation and the residue is taken up in 20 ml of ethyl acetate. The organic solution is washed with 10 ml each of saturated aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.52.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(OCC)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:38][C:39]([F:42])([F:41])[F:40].CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][C:20]=2[O:38][C:39]([F:42])([F:40])[F:41])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(OC(F)(F)F)c2)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)c(OC(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.110 g, 0.506 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (10 mL) at 0° C. A 1.0 M ZnCl2 solution in diethyl ether (0.578 mL, 0.578 mmol) was added cautiously, after addition the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl 4-(4-amino-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I47) (impure, ˜80% pure, 0.217 g, 0.482 mmol) in 1:1 t-BuOH:1,2-dichloroethane (5 mL) was added drop-wise at 0° C. followed by a solution of NEt3 (0.081 mL, 0.58 mmol) in 1:1 t-BuOH:1,2-dichloroethane (5 mL) and the reaction was allowed to warm to room temperature and was stirred for 18 hours, then at 60° C. for 24 hours. The organic solvents were evaporated vacuo and the crude gum was purified by silica gel chromatography (40 g Si cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I48) (0.085 g, 33% yield) as a pale yellow oily solid; 1H NMR (400 MHz, d6-DMSO) δ 10.38 (s, 1H), 8.72 (s, 1H), 7.52 (cl, J=8.1 Hz, 1H), 7.33-7.29 (m, 2H), 4.13-4.04 (m, 2H), 2.88-2.72 (m, 3H), 1.79 (d, J=12.1 Hz, 2H), 1.56-1.44 (m, 2H), 1.42 (s, 9H). LCMS Method C: rt 7.02 min; m/z 539.0, 541.0 [M−H]−.
Reaction SMILES: C(O[C@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]=[N+:25]=[N-:26])(=O)C.[BrH:27]>C(Cl)Cl.[Br-].C([N+](CC)(CC)CC)C>[C:9]([O:8][C@H:7]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@H:5]([Br:27])[C@@H:6]1[N:24]=[N+:25]=[N-:26])(=[O:11])[CH3:10]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Br
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 2 h

Procedure:
1 ,3,4,6- Tetra-O-acetyl-2-azido-2-deoxy-alpha-D-galactopyranose (14) (500 mg) was dissolved in 50 mL CH2Cl2 (anhydrous), treated with 50 mL of CH2Cl2 saturated with HBr at 0° C., and stirred for two hours. Then 2 g of tetraethyl ammonium bromide was added and stirred overnight. Next, the solution was washed with 100 mL ice-cold water and concentrated. The residue was crystallized from ethyl ether and pentane to give 400 mg of 3,4,6-tri-O-acetyl-2-azido-2-deoxy-alpha-D-galactopyranosyl bromide (18).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 471 (M+H). 1H NMR (500 MHz, CD3OD) δ 8.90-6.60 (m, 8H), 5.15-3.00 (m, 5H), 2.45-0.65 (m, 11H).
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:9].[C:13]([O:17][C:18]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[CH:8]([C:7]1[CH:10]=[CH:11][N:12]=[C:5]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:24]=[CH:23][CH:22]=2)[CH:6]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=Cc1ccnc(Br)c1
Agent: OBO
Product: CC(C)(C)OC(=O)n1cccc1-c1cc(C=O)ccn1

Procedure:
tert-butyl 2-(4-formylpyridin-2-yl)-1H-pyrrole-1-carboxylate was prepared using the general boronic acid coupling procedure for 2-bromoisonicotinaldehyde and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (56 mg, 146.5 mg theoretical, 38.2%). LC-MS m/z 273.3 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]>C1COCC1.CO.O.[Li+].[OH-]>[C:27]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]3[CH2:21][CH2:22][C@@H:23]([F:26])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)[C@H]2CC[C@@H](F)CC2)CC1

Procedure:
5-cyclohex-1-enyl-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10 mg, 0.021) was dissolved in a mixture of THF, MeOH and H2O (3:2:1) (2 mL) and 1N LiOH (0.1 mL) was added. Rest of the procedure has been described earlier (example 3, step VIII). Pure 5-cyclohex-1-enyl-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid was obtained after chromatography over silica gel (5% MeOH in DCM as eluent) (5 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:28](=[O:30])[CH3:29])[N:12]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)CCCCc1nc(-c2ccccc2N)co1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCc1nc(-c2ccccc2NC(C)=O)co1
Temperature: 25 °C

Procedure:
Dissolve 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (4.05 g, 14.8 mmol) and triethylamine (2.26 mL, 16.2 mmol) in TI-IF (40 mL) and stir at room temperature. Add acetyl chloride (1.16 mL, 16.2 mmol) and allow the mixture to stir overnight at room temperature. Concentrate the mixture and partition the residue between aq NaHCO3 and EtOAc. Dry the combined extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) which allows for the isolation of 5-[4-(2-acetylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.51 g, 75%). MS (ES): (M+1)+ 317.2 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC=C(c1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCC(c1ccccc1)c1ccc(Cl)c(Cl)c1
Yield: 100 %

Procedure:
A solution of 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (223 g., 0.73 mole) in ethyl acetate (2 l.) was hydrogenated over 8 grams of 5% Pd/C catalyst at atmospheric pressure and room temperature until hydrogen uptake ceased (about 24 hours). The catalyst was separated by filtration and the filtrate evaporated under vacuum to a light brown oil containing traces of solvent (ca. 100% yield). An analytical sample of the named compound was crystallized from hexane (m.p. 118°-120° C., elemental analysis calculated: 62.17% C; 4.57% H; 22.94% Cl; found: 62.08% C; 4.56% H; 23.16% Cl).
Reaction SMILES: [Br:1][C@@H:2]1[C@:6](C(=O)C)([OH:7])[C@@H:5]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[O:4][C@H:3]1[N:16]1[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18].O.NN.Cl>O.C(#N)C>[Br:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[O:4][C@H:3]1[N:16]1[CH:23]=[C:22]([CH3:24])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](Br)[C@@]1(O)C(C)=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](Br)[C@@H]1O
Temperature: 0 °C
Yield: 92.9 %

Procedure:
400 ml of acetonitrile and 2.16 g (3 equivalents) of water were added to 16.2 g (40.0 mmol) of 2'-deoxy-2'-bromo-3',5'-O-diacetyl-5-methyluridine, and the mixture was stirred. The resulting solution was cooled to 0° C., 6.01 g (3 equivalents) of hydrazine monohydrate were added thereto, and the mixture was reacted for 20 hours at that temperature. 100 ml of water were added to the reaction mixture, which was then neutralized to a pH of 6.8 by adding 6 N-hydrochloric acid thereto. The acetonitrile layer was separated, washed with saturated saline solution, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 13.5 g of 2'-deoxy-2'-bromo-5'-O-acetyl-5-methyluridine. Its purity was 81.8%. Its yield was 76.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:9][N:8]=1)=[O:5].[CH2:33]([N:35]([CH2:50][CH3:51])[CH2:36][CH2:37][N:38]([CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])[CH3:39])[CH3:34].CCN=C=NCCCN(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:50]([N:35]([CH2:33][CH3:34])[CH2:36][CH2:37][N:38]([CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44]([NH:1][C:2]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)=[CH:9][N:8]=1)=[O:5])=[O:45])[CH3:39])[CH3:51]
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ncc(-c2cccc(C(F)(F)F)c2)cn1
Reactant: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3cccc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 10.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)benzamide (200 mg, 0.45 mmol, 1.00 equiv) in dichloromethane (5 mL), 3-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (120 mg, 0.45 mmol, 1.00 equiv), EDCI (130 mg, 0.68 mmol, 1.50 equiv), and 4-dimethylaminopyridine (83 mg, 0.68 mmol, 1.50 equiv). The resulting solution was stirred for 10 h at 25° C. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 32.2 mg (9%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 11.45 (s, 1H), 11.29 (s, 1H), 9.18 (s, 2H), 8.12-8.21 (m, 3H), 8.03 (s, 1H), 7.89-7.91 (d, J=6.6 Hz, 1H), 7.75-7.84 (m, 2H), 7.62-7.66 (m, 2H), 7.51 (s, 1H), 7.28-7.31 (d, J=8.1 Hz, 1H), 3.37 (s, 2H), 3.26 (s, 4H), 3.10-3.18 (m, 4H), 1.58-1.68 (m, 6H), 1.15-1.20 (m, 6H). MS (ES, m/z): 688.00 [M+]+.
Reaction SMILES: [CH:1]1([C:7]2([OH:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:22][C:23](=[O:45])[C@H:24]([CH2:43]O)[NH:25]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH:1]1([C:7]2([O:20][CH2:43][C@@H:24]([C:23]([OH:45])=[O:22])[NH2:25])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OC1(C2CCCCC2)c2ccccc2-c2ccccc21
Product: N[C@@H](COC1(C2CCCCC2)c2ccccc2-c2ccccc21)C(=O)O

Procedure:
from 9-cyclohexyl-9H-fluoren-9-ol (Example 1r) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:19])[C:12](=[CH:17][CH:18]=1)[C:13](OC)=[O:14]>CCOCC>[OH:19][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[CH:18]=[CH:17][C:12]=1[C:13]([NH:2][OH:3])=[O:14]
Reactant: NO
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(=O)NO)c(O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Prepare 4-(6-methoxybenzo[d]isoxzaol-3-yl)piperazine by slowly adding a solution of hydroxylamine hydrochloride (57.2 g, 0.823 mol) and water (600 mL) to a solution of sodium hydroxide (76.9 g, 1.92 mol) and water (300 mL). Then add a solution of methyl 4-methoxysalicylate (100 g, 0.55 mol, Aldrich Chemical Co.) and ether (800 mL), stir overnight, evaporate the ether, acidify with dilute hydrochloric acid, cool to 0° C., and filter. Recrystallize the filter cake from methanol to afford the 2-hydroxy-p-anisohydroxamic acid (78 g). Treat a warm (50° C.) solution of the hydroxamic acid (78 g) and tetrahydrofuran (500 mL) under nitrogen with a solution of carbonyldiimidazole (138.1 g, 0.85 mol) and tetrahydrofuran (500 mL), reflux for 3.5 hours, quench by addition of water (1000 mL), acidify to pH 3, add water (1000 mL) and refrigerate overnight. Collect the solid, wash with water and recrystallize from methanol to afford 54 g of 3-hydroxy-6-methoxy-1,2-benzisoxazole. Heat a stirred mixture of 3-hydroxy-6-methoxy-1,2-benzisoxazole (54 g) and POCl3 (100.3 g, d 1.645) at 95° C. under nitrogen, cool to 30° C., add triethylamine (33 g), heat at 140° C. overnight, quench with stirring into ice water and filter. Dissolve the filter cake in cyclohexane (2000 mL), filter, concentrate and recrystallize the residue from petroleum ether to give 3-chloro-6-methoxy-1,2-benzisoxzole (33 g). Treat this product with piperazine as described in U.S. Pat. No. 5,852,022, the contents of which are herein incorporated by reference, to afford 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20](O)=[O:21])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([C@H:63]([CH3:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66])=[CH:59][CH:58]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19][C:20]([NH:56][C:57]2[CH:58]=[CH:59][C:60]([C@H:63]([CH3:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66])=[CH:61][CH:62]=2)=[O:21])[CH:3]=1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Reactant: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)O)cc2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2cc(C)c3nc(Nc4ccccc4C)oc3c2)cc1
Yield: 91.5 %

Procedure:
A stirred solution of 2-(4-methyl-2-o-tolylaminobenzoxazol-6-yl)acetic acid [0.1 g, Reference Example 9(b)] in dimethylformamide (3 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.128 g), diisopropylethylamine (0.22 g) and after 5 minutes with ethyl (R) 3-(4-aminophenyl)butanoate (0.107 g, Reference Example 1). After 4 hours the reaction mixture was diluted with ethyl acetate and then washed with water, then with hydrochloric acid (1M), then twice with water, then with brine, then dried and then evaporated to give the title compound (0.15 g) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:16](OCC)=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]3[C:16]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)=[N:1][C:2]4[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=4[NH:4][C:5]=3[S:9][C:8]=2[CH:10]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2ccccc2N)sc2cc(OC)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: COc1ccc2c3c(sc2c1)Nc1ccccc1N=C3N1CCN(C)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-aminoanilino)-6-methoxybenzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10]([Cu])#[N:11]>CN1C(=O)CCC1>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:10]#[N:11]
Reactant: N#C[Cu]
Reactant: Cc1ccc(N)c(Br)c1
Solvent: CN1CCCC1=O
Product: Cc1ccc(N)c(C#N)c1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
Combine 2-bromo-4-methyl-phenylamine (8.00 g, 43.0 mmol), CuCN (4.62 g, 51.6 mmol), and NMP (30.0 ml). Stir the mixture at reflux for 75 minutes then cool it to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting precipitate by vacuum filtration. Dissolve the precipitate in NH4OH and extract it with dichloromethane. Combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/hexanes (75:25) to give 3.39 g (60%) of an orange solid: mass spectrum (ion spray): m/z=133.1 (M+1).
Reaction SMILES: CO[C:3](=[O:22])[C:4]([OH:21])=[CH:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]#[N:19])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:31][N:32](C)[C:33](C1CN(C)C(=O)C=1O)=O>>[C:18]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:31][N:32]([CH3:33])[C:3](=[O:22])[C:4]=1[OH:21])=[O:20])#[N:19]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(C#N)c1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)c(C#N)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 69 %

Procedure:
3-[(3-Cyano-4-fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 61-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (69% yield); mp 175° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.78 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.85 (2H, s, NCH2), 7.19–7.24 (1H, m, aromatic), 7.59–7.62 (2H, m, aromatics).