Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39](=[O:61])[N:40]([CH2:51][CH2:52][O:53][Si](C(C)(C)C)(C)C)[CH2:41][CH2:42][O:43][Si](C)(C)C(C)(C)C)=[CH:33][CH:32]=1)[C:9](=[O:30])[NH:10][CH:11]([C:20]1[NH:24][C:23]2[CH:25]=[C:26]([I:29])[CH:27]=[CH:28][C:22]=2[N:21]=1)[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39](=[O:61])[N:40]([CH2:51][CH2:52][OH:53])[CH2:41][CH2:42][OH:43])=[CH:35][CH:36]=1)[C:9]([NH:10][C@H:11]([C:20]1[NH:24][C:23]2[CH:25]=[C:26]([I:29])[CH:27]=[CH:28][C:22]=2[N:21]=1)[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:30]
Reactant: CC(c1ccccc1)C(NC(=O)C(NC(=O)OC(C)(C)C)c1ccc(OCC(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc1)c1nc2ccc(I)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OCC(=O)N(CCO)CCO)cc1)c1nc2ccc(I)cc2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
{[4-({Bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-carbamoyl}-methoxy)-phenyl]-[1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (270 mg, 0.27 mmol) was dissolved in dry dichloromethane (6 mL) and cooled in an ice bath. To the stirred solution was added triflouroacetic acid (3.12 mL, 40.5 mmol). The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane (1 mL) and the crude trifluoroacetate salt precipitated with ether (5 mL) and pentane (10 mL). The precipitate was triturated then filtered. The solid was taken into dichloromethane (50 mL) and tetrahydrofuran added to form a clear solution. The solution was washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), the layers separated and the aqueous layer extracted with dichloromethane (4×50 mL). The combined organic extracts were dried over sodium sulfate filtered and concentrated in vacuo. The resulting solid was triturated with a mixture of ether (1 mL) and pentane (5 mL), filtered and dried to give (R)-2-amino-2-(4-{[bis-(2-hydroxy-ethyl)-carbamoyl]-methoxy}-phenyl)-N-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-acetamide (170 mg, 93.8%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)(C)C(Cl)=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(N(CC)CC)C>[C:38]1([NH:37][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[CH2:10][CH:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:18][CH2:17]4)=[CH:29][CH:28]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccccc1
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Triethylamine (0.11 ml) was added to THF suspension (3 ml) of 4-[[2-(2-piperidinoethyl)-6-tetralinyl]oxymethyl]benzoate (300 mg). Further, THF solution (0.5 ml) of trimethylacetyl chloride (92 mg) was added dropwise under ice-cooling, which was stirred for 30 minutes. The temperature of the reaction mixture was raised to room temperature, which was stirred for 1 hour. THF solution (0.5 ml) of aniline (85 mg) was added dropwise to the reaction mixture under ice-cooling, which was stirred for 1 hour. After the reaction mixture was stirred for 24 hours at room temperature, saturated sodium bicarbonate solution was added, and extraction was conducted using a mixed solution of ethyl acetate and THF. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized from THF-methanol-IPE to give the titled compound (150 mg).
Reaction SMILES: Cl.[CH2:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22]C)[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:3][CH3:4].CO>O>[CH2:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:3][CH3:4]
Reactant: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: Cl
Solvent: O
Solvent: CO
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Yield: 13.7 %

Procedure:
Add 3N hydrochloric acid (1 cc.) to a solution of 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.61 g.) in boiling methanol (70 cc.) and cool the mixture immediately and allow to stand for 41/2 hours. Pour the product into water (300 cc.) and extract the mixture with ether; work up in the usual way to give as residue an amorphous solid (0.6 g.). Crystallize this solid from a mixture of ether and hexane. Take up the resulting solid in benzene (20 cc.) and chromatograph on a column of neutral alumina. Elute the product with ether and recrystallize from a mixture of ether and hexane to obtain 13β-n-propyl-17β-hydroxy-gon-4-en-3-one (0.08 g.), mp. 126°-7°; ultraviolet absorption peak at 240 mμ (ε15,000); infrared absorption peaks at 2.92, 6.01, 6.20 μ. Evaporation of the mother liquors gives a second, polymorphic, form of the same substance (0.17 g.), m.p. 144°-5° , having ultraviolet and infrared spectra identical with the first material; a mixture of the two forms has m.p. 144°-5°.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:16](C(=O)C)[CH2:15][CH:14](C(=O)C)[CH:13]1[C:23]#[N:24])([O:3][CH2:4][CH3:5])=[O:2].ClC1C=CC=[C:28]([C:32]([O:34]O)=[O:33])C=1.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:16]([O:3][C:1](=[O:2])[CH3:6])[CH2:15][CH:14]([O:34][C:32](=[O:33])[CH3:28])[CH:13]1[C:23]#[N:24])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCCCCC1C(C(C)=O)CC(C(C)=O)C1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCCC1C(OC(C)=O)CC(OC(C)=O)C1C#N
Reaction time: 96 h
Yield: 73 %

Procedure:
Five hundred milligrams of 2-(6'-carboethoxyhexyl)-3,5-diacetyl-cyclopentanecarbonitrile and 600 mg of meta-chloroperbenzoic acid were dissolved in 30 ml of chloroform, and the solution was allowed to stand for 4 days at room temperature. The reaction mixture was then treated with a 5% solution of sodium iodide and then with a 10% solution of sodium thiosulfate. Five hundred (500) milligrams of the resulting oily substance was purified by chromatography on silica gel to yield 200 mg of 2-(6'-carboethoxyhexyl)-3,5-diacetoxy-cyclopentanecarbonitrile which has the following characteristics: Infrared absorption (film method): 2250, 1735, 1235, 1180; Nuclear magnetic resonance (in CDCL3 solvent): the absorption of the methyne protons at the 3- and 5-position were observed at about 4.9 and about 5.2; 4.10 (2H, multiplet signal), 2.05 (6H, two singlet signals acetoxymethyl proton).
Reaction SMILES: O.[ClH:2].C([S:7][CH2:8][C@@:9]([CH3:14])([C:11]([OH:13])=[O:12])[NH2:10])(C)(C)C>C(O)(C)C>[ClH:2].[CH3:14][C@@:9]([C:11]([OH:13])=[O:12])([CH2:8][SH:7])[NH2:10]
Reactant: CC(C)(C)SC[C@](C)(N)C(=O)O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: C[C@](N)(CS)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
First, water (47.6 g) and conc. hydrochloric acid (177.4 g) were added to S-tert-butyl-α-methyl-L-cysteine (25 g, 131 mmol) produced by the method of EXAMPLE 11, and the resultant mixture was refluxed for 41 hours. Furthermore, conc. hydrochloric acid (47.6 g) was added to the mixture, followed by reflux for 3 hours. After the mixture was allowed to cool down to room temperature, isopropyl alcohol (90 mL) was added to the mixture, followed by vacuum concentration. Then, azeotropic dehydration was performed three times using the same amount of isopropyl alcohol. Finally, isopropyl alcohol was added to the residue, and the resultant mixture was concentrated to a volume of about ⅓. Then, the residue was heated to 60° C., and toluene (90 mL) was added to the residue. After the mixture was allowed to cool down to room temperature under stirring, stirring was continued about 1 hour. Then, the precipitated crystals were filtered off, washed with toluene, and dried under reduced pressure to obtain the title compound as a white solid (13.5 g, yield 60.0%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:30])[CH:10]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:31](OC(=O)C)(=O)[CH3:32].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:31][C:32]1[O:1][C:2]2[C:3]([C:9](=[O:30])[CH:10]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(=O)c2cccc(C)c2o1
Temperature: 25 °C

Procedure:
27.5 g (67 mmol) of 1-(2-hydroxy-3-methylphenyl)-2-(triphenylphosphoranylidene)ethanone in 200 ml of absolute toluene are heated to reflux. 13.7 g (134 mmol) of acetic anhydride and 11.1 g (141 mmol) of pyridine are slowly added dropwise to this solution. The reaction mixture is then heated under reflux for 6 h. After cooling to room temperature, the solution is washed with saturated sodium carbonate solution and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: cyclohexane/ethyl acetate 7:3→4:6). 7.5 g (64% of theory) of the title compound are obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:32]C(=O)OC(C)(C)C)[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH:30]=3)[S:24][C:17]=12>>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[CH:22]=[C:23]([C:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH:30]=3)[S:24][C:17]=12)[NH2:32]
Reactant: CN1CC=C(c2cc3nccc(Oc4ccc(NC(=O)OC(C)(C)C)cc4F)c3s2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
TFA (1 mL) was added to tert-butyl 3-fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamate (229) (105 mg, 0.23 mmol) and the mixture was stirred for 1 h at room temperature. The solution was concentrated under reduced pressure, the residue co-distilled with MeCN, redissolved in MeOH and purified by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) giving 230 (50 mg, 0.1 mmol, 48% yield) as a white solid. MS (m/z): (M+1) 356.1 (100%).
Reaction SMILES: C(O[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:18])[CH3:17])=[C:11]([O:19][CH2:20][CH3:21])[CH:10]=1)[C:6]([OH:8])=[O:7])(=O)C.O>CO.[OH-].[OH-].[Pd+2]>[C:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:5][C:6]([OH:8])=[O:7])=[CH:10][C:11]=1[O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]
Reactant: CCOc1cc(C(OC(C)=O)C(=O)O)ccc1OC(C)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cc(CC(=O)O)ccc1OC(C)=O
Yield: 88.8 %

Procedure:
Intermediate 3 (30.9 g, 0.104 mol) was dissolved in methanol (500 mL), Pd(OH)2 (5.0 g) wet with distilled water was added, and the mixture was placed under hydrogen at 30 psi with shaking. After 48 hr Pd(OH)2 was removed by filtration and solvent was removed under vacuum giving 22 g of intermediate 4 as a yellow oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:45])[CH2:31][CH2:32][N:33]([S:41]([CH3:44])(=[O:43])=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>>[CH3:29][N:30]([CH3:45])[CH2:31][CH2:32][N:33]([C:34]1[CH:35]=[CH:36][C:37]([NH:40]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:38][CH:39]=1)[S:41]([CH3:44])(=[O:43])=[O:42]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.3 (aluminium oxide, methylene chloride/ethanol=40:1) C29H32N4O5S
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])=[O:17].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:17])[C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:59]2[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]2)=[O:24])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Yield: 99.4 %

Procedure:
4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-nitrobenzoic acid (500 mg, 1.11 mmol) in DMF (10 mL) was treated with 1-hydroxybenzotriazole (195 mg, 1.44 mmol), EDCI (276 mg, 1.44 mmol) and 1-methylpiperazine (0.16 mL, 1.44 mmol). The reaction was left at room temperature over night. The volatiles were removed by evaporation, the residue was added drop-wise to iced-water (25 mL) with stirring. A yellow solid was obtained which was extracted with DCM (2×25 mL). The combined organic layers were dried over sodium sulphate and evaporated leaving 590 mg of title compound which was employed in the following step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:26])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2ccc(Br)cc2)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude benzhydryl alcohol (53.2 g, 135 mmol) was dissolved in 1000 mL of dichloromethane and 14.7 mL (202 mmol) of thionyl chloride was added dropwise. The solution was stirred overnight at room temperature and the solvent was removed under vacuum. The crude product was redissolved in 500 mL of toluene and the solvent again was removed under vacuum to eliminate excess thionyl chloride, providing crude α-(4-bromophenyl)-3-(tert-butyldimethylsilyoxy) benzyl chloride as a dark oil. NMR (200 MHz, CDCl3): δ0.2 (s,6H); 1.0 (s,9H); 6.0 (s,1H); 6.78 (dd,J1 =1 Hz,J2 =8 Hz,1H); 6.9 (m,2H); 7.2 (t,J=8 Hz,2H); 7.27 and 7.47 (AB q,J=8 Hz,4H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([CH2:31][CH2:32][O:33][CH2:34][CH3:35])[C:28](=[O:36])[N:27]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>ClCCl.C(OCC)C>[ClH:42].[CH:37]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][CH2:34][CH3:35])[C:28]2=[O:36])[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CCOCCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCCc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
4-{6-[8-Cyclopentyl-6-(2-ethoxy-ethyl )-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.325 g, 0.577 mmol) was dissolved in dichloromethane (4 mL). 2 N HCl in diethyl ether (4 mL) was added and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated to give 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-(5-piperazin-1-yl-pyridin-2ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.292 g, 97.7%). MS (APCl) Calc'd for M+H: 449.2. Found: 449.2. Anal. Calc'd for C25H33N7O22.6HCl,0.35H2O: C, 52.26; H, 6.56; N, 16.88. Found: C, 52.01; H, 6.96; N, 16.88.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.O.[C:14](OCC)(=O)C>CO.Cl>[CH3:1][O:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[CH:6][CH:5]=1
Reactant: COCc1ccc(C(=O)O)cc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: COCc1ccc(C(=O)OC)cc1
Reaction time: 2.5 h

Procedure:
Methyl 4-(methoxymethyl)benzenecarboxylate (MMBC) was prepared from 4-(methoxymethyl)benzoic acid (Sigma-Aldrich) by esterification in methanol using HCl as catalyst. The reaction was conducted under reflux conditions for 2.5 hours. Following the reaction, water and ethyl acetate was added and the MMBC product was separated using liquid extraction into the ethyl acetate phase. The ethyl acetate was then removed by rotary evaporation to obtain the isolated MMBC product. The 1H NMR spectrum of the product was collected in CDCl3, and the peak positions and integrated areas matched that of the reported 1H NMR spectrum for this molecule.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:14][CH:13]([CH3:15])[CH2:12][O:11][CH2:10][C:9]2=O)=[CH:5][CH:4]=1.CO.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:14][CH:13]([CH3:15])[CH2:12][O:11][CH2:10][CH2:9]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CN2CC(C)COCC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CCOCC(C)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
To a solution of 4-(4-methoxy-benzyl)-6-methyl-[1,4]oxazepan-3-one (4.35 g, 17.5 mmol) in tetrahydrofuran (10.0 ml) was added 1M borane-tetrahydrofuran complex in tetrahydrofuran (52.3 ml, 52.3 mmol) at 0° C. The mixture was stirred at room temperature for 4 hours. After cooling to 0° C., methanol (20 ml) and 6N sodium hydroxide aqueous solution (30 ml) was added carefully. The mixture was refluxed for 2 hours and cooled to room temperature. The organic solvent was removed under reduced pressure. The residue was partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant; hexane/ethyl acetate=1/1) to afford 4-(4-methoxy-benzyl)-6-methyl-[1,4]oxazepane as colorless oil (3.24 g, 79%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:45])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([C:30]1[NH:34][C:33]3[CH:35]=[CH:36][C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:38][C:32]=3[N:31]=1)=[N:18][N:19]2C1CCCCO1)=[O:13]>C(Cl)Cl>[F:45][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([C:30]1[NH:31][C:32]3[CH:38]=[C:37]([N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)[CH:36]=[CH:35][C:33]=3[N:34]=1)=[N:18][NH:19]2)=[O:13]
Reactant: O=C(Nc1cccc2c1c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc2[nH]nc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)c12)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
TFA (327 mg, 2.87 mmol) was added to solution of 2,2-difluoro-N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)cyclopropane carboxamide (15 mg, 0.029 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (8 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.18 (d, 1H, J=8.0 Hz), 7.49 (d, 1H, J=8.8 Hz), 7.35 (m, 1H), 7.25 (d, 1H, J=8.0 Hz), 7.18 (s, 1H), 7.09 (d, 1H, J=7.6 Hz), 3.89 (m, 4H), 3.22 (m, 4H), 3.08-3.01 (m, 1H), 2.21-2.15 (m, 1H), 1.96 (m, 1H); ESI-MS [M+H]+: 439.1.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[C:9]1([CH2:15][S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([NH:21][NH2:22])=[O:20])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1>[C:9]1([CH2:15][S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]2[O:20][C:2](=[O:3])[NH:22][N:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NNC(=O)c1ccccc1SCc1ccccc1
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccccc2SCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution containing 12.2 g of trichloromethyl chloroformate in 130 ml of p-dioxane was added portionwise 16 g of 2-[(phenylmethyl)thio]benzoic acid, hydrazide [prepared by the procedure of South African Patent Application No. 838,416 (1983)] to cause a slight exotherm to 37° C. After stirring at ambient temperature for 0.5 hr., the suspension was refluxed for 6 hours, then cooled to 25° C. and poured onto excess ice/water to yield a precipitate. The mixture was filtered, washed with water and the isolated solid was recrystallized from acetonitrile to yield 14 g of the subject compound: m.p. 169°-172° C.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCOc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCOc3ccc(N)cc3)CC2)cc1
Yield: 66.4 %

Procedure:
The compound of Example 1 (2.00 g, 4.47 mmol) and tin (II) chloride dihydrate (8.06 g, 35.75 mmol) were stirred together in ethanol (30 mL) at 70° C. for 6 hours. The solvent was removed in vacuo and the residue was partitioned between 10% aqueous sodium bicarbonate and 4:1 dichloromethane/isopropanol. The organic phase was dried (MgSO4) and concentrated to afford 1.24 g (66%) of N-[4-[[1-[2-(4-aminophenoxy)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide as a white foam which was used directly in the next step. 1H NMR (CDCl3); δ7.85 (d, J=6 Hz, 2H), 7.23 (d, J=6 Hz, 2H), 6.63 (m, 4H), 4.21 (br s, 2H), 4.00 (m, 2H), 3.18 (m, 3H), 3.00 (s, 3H), 2.79 (m, 2H), 2.20 (m, 2H), 1.80 (m, 4H).