Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[OH:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: Oc1cccc(OCC2CCC3(CC2)OCCO3)c1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(COc2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
To a solution of 3-(1,4-dioxaspiro[4.5]dec-8-ylmethoxy)phenol (536 mg) in acetone (9.6 mL) was added 1M hydrochloric acid (9.6 mL), followed by stirring at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and then water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4-[(3-hydroxyphenoxy)methyl]cyclohexanone (446 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.S(Cl)([Cl:29])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:29])=[O:18])=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCCCCCOc2cc(F)c(F)c(F)c2)cc1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCCCCCCOc2cc(F)c(F)c(F)c2)cc1
Temperature: 35 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
About 10 g (about 27.148 mmol) of 4-[6-(3,4,5-Trifluoro-phenoxy)-hexyloxy]-benzoic acid was dissolved in about 200 ml of methylene chloride, and then added with about 3.55 g (about 29.862 mmol) of thionyl chloride. The reaction mixture was stirred at about 35° C. for about 6 hours, and the solvent was removed. Through a vacuum drying process, the desired compound was obtained (Yield about 95%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]=2[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[CH2:22]([N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]1=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2c(c1)N(Cc1ccccc1)C(=O)CO2
Temperature: 100 °C

Procedure:
Methyl 2 oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (50 mg, 240 μmol) was dissolved in DMF (0.5 mL) in a 2 mL microwave vial containing a magnetic stirrer bar. Potassium carbonate (100 mg, 720 μmol) was added to the vial followed by benzyl bromide (62 mg, 360 μmol) and tetrabutylammonium iodide (10 mg, 27 μmol). The vial was capped and was heated to 100° C. by microwave irradiation for 5 minutes. The reaction mixture was diluted with EtOAc (3 mL) and of saturated aqueous sodium bicarbonate (3 mL). The organic layer was removed and the aqueous layer was extracted with 2 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 filtered and evaporated. This yielded 70 mg of a yellow oil which was used without further purification. LCMS (+ESI) m/z=299.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:12]=2[NH:20][C:21](=[O:35])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:23]=2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:37][C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=1>>[N:29]1([CH2:28][C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:12]2[S:13][C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:11]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:37][C:38]3[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=3)=[CH:7][CH:6]=2)=[O:10])=[O:35])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C(Nc1sc2c(c1C(=O)Nc1ccc(O)cc1)CCCC2)c1cccc(CN2CCOCC2)c1
Product: COC(=O)c1ccc(COc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN5CCOCC5)c4)sc4c3CCCC4)cc2)cc1
Yield: 87.8 %

Procedure:
By using 169 mg of N-(4-hydroxyphenyl)-2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide and 95 mg of methyl 4-(bromomethyl)benzoate, 193 mg of methyl 4-[(4-{[(2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenoxy)methyl]benzoate was obtained by the method similar to Preparation Example 30.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:3]1.[C:21]([O-])([O-])=O.[K+].[K+].CC(C)=O.IC>C(OCC)(=O)C>[CH3:21][N:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[B:4]1[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1)[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1ccccc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a round bottom flask under nitrogen were added N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (250 mg, 0.84 mmol), K2CO3 (140 mg, 1.01 mmol) and acetone (5.0 mL). Iodomethane (0.06 mL, 1 mmol) was then added to the mixture dropwise and the reaction stirred for 18 hours at rt. The reaction was then diluted with ethyl acetate (100 mL), washed with water (2×) and brine (1×), dried (Na2SO4) and concentrated to dryness. The crude product was purified by FCC providing the title compound (230 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J=7.3, 1.8, 1H), 7.51-7.43 (m, 1H), 7.40-7.29 (m, 2H), 3.32 (s, 3H), 2.93 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[NH:6]([S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8]>O>[NH:6]([S:7]([C:10]([F:13])([F:11])[F:12])(=[O:9])=[O:8])[S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15].[NH:6]([S:7]([C:10]([F:13])([F:11])[F:12])(=[O:9])=[O:8])[S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15].[Ca:5]
Reactant: [Ca+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: [Ca]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.0 g of calcium(II) carbonate was suspended in 50 mL of water, to which freshly prepared HNTf2 (5.6 g) was added and stirred at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated on a rotary evaporator and dried under vacuum (1 mmHg) for 4 hours at 150° C. The unpurified calcium bis-triflimide was found to display poor catalytic activity in Friedel-Crafts reactions.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=[CH:11][C:10]=3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Br)=[O:33])=[CH:30][CH:29]=1>ClCCl>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([C:9]2[C:10]3[CH:11]=[N:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][C:15]=3[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=3)[CH:8]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Br)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc2c(ccn2Cc2ccc(F)cc2)cn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(cn1)c(C(=O)c1ccc(F)cc1)cn2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.1 %

Procedure:
To a stirred solution of ethyl 1-(4-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (4.0 g, 13.4 mmol) in dichloromethane (60 mL) were added aluminum chloride (3.6 g, 26.8 mmol) and 4-fluorobenzoyl bromide (3.2 mL, 26.8 mmol). The resulting mixture was stirred for three days at ambient temperature. It was quenched with ice-water (100 mL), and extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with water (2×100 mL), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. Elution with hexane:ethyl acetate (1:1) provided the title compound as a solid (2.2 g, 39% yield). 1H NMR (CDCl3) δ ppm 9.62 (s, 1H), 8.23 (s, 1H), 7.85-7.87 (m, 2H), 7.74 (s, 1H), 7.12-7.18 (m, 4H), 7.03-7.06 (m, 2H), 5.43 (s, 2H), 4.51 (q, 2H, J=7.2 Hz), 1.47 (t, 3H, J=7.2 Hz). LCMS (APCI, M+H+): 421.1.
Reaction SMILES: [CH2:1]([N:4]1[C:9]([CH2:10][OH:11])=[CH:8][C:7](=[O:12])[C:6]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5]1)[CH:2]=[CH2:3]>[O-2].[O-2].[Mn+4]>[CH2:1]([N:4]1[C:9]([CH:10]=[O:11])=[CH:8][C:7](=[O:12])[C:6]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Product: C=CCn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1C=O

Procedure:
Starting from 1.000 g of 1-allyl-3-diphenylmethoxy-6-hydroxymethyl-4-pyridone and 6.00 g of manganese dioxide, the title compound is obtained in the same manner as in Synthesis Example 2 as colorless crystal in a yield of 0.710 g.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:7][NH:6][CH2:5]1.N12CCCNC1CCCC=C2.[NH2:19][C:20]1[N:25]=[C:24]([N:26]2[C:35]3[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=3[CH3:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]2)[C:23]([F:43])=[CH:22][C:21]=1[F:44]>N1C=CC=CC=1>[NH2:3][CH:4]1[CH2:7][N:6]([C:33]2[C:34]([CH3:36])=[C:35]3[C:30]([C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27][N:26]3[C:24]3[C:23]([F:43])=[CH:22][C:21]([F:44])=[C:20]([NH2:19])[N:25]=3)=[CH:31][C:32]=2[F:38])[CH2:5]1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c12
Reactant: NC1CNC1
Agent: C1=CN2CCCNC2CCC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(N2CC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c12
Temperature: 100 °C
Reaction time: 0.1 h
Yield: 10.3 %

Procedure:
A solution of 70 mg of 3-aminoazetidine dihydro-chloride, 200 mg of 1,8-diazabicyclo[5,4,0]undecene, and 300 mg of pyridine was stirred at 100° C., and 110 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added to the solution and the solution was stirred at 100° C. for 6 minutes. The solvent was distilled off the reaction solution, and to the residue was added one drop of acetic acid and 3 ml of ethanol with heating, and the solution was allowed to stand. The solid precipitate was collected and dried to obtain 13 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([C@@H:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:44][C:32]1[N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:25][CH:26]=2)[C:39]2[C:34]([C:33]=1[CH3:43])=[CH:35][C:36]([C:40](=[O:41])[NH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][CH3:2])=[CH:37][CH:38]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC[C@@H](N)c1ccccc1
Product: CC[C@@H](NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (R)-α-ethylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].Cl[CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1>>[CH3:15][N:14]1[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=[C:10]1[CH2:9][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: CC#C[Si](C)(C)C
Product: Cn1c(CCC#C[Si](C)(C)C)nc2ccccc21
Yield: 58.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 67(D), from trimethyl(prop-1-ynyl)silane (283 mg, 2.52 mmol) and 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (380 mg, 2.10 mmol). The crude product was purified over prepacked 25 g silicagel column (DCM/MeOH from 100/0 to 98/2 as eluent) to afford 317 mg of 1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (Yield: 59%) as red solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=3)[C:18]=1[S:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:8]2.[OH-].[Na+]>CO>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:27][CH:28]=3)[C:18]=1[S:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:8]2
Reactant: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(CC(=O)O)cc1
Reaction time: 8 h
Yield: 31 %

Procedure:
Methyl 2-[4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetate (Intermediate #34) (220 mg, 0.47 mmol) was dissolved in methanol (10 mL) and treated at ambient temperature with a 2M solution of sodium hydroxide (1.17 mL, 2.35 mmol). The mixture was stirred overnight and then methanol was removed by evaporation under reduced pressure. The clear aqueous solution was diluted with water (20 mL) and acidified to pH3 with 2M HCl. The resulting white precipitate was extracted into ethyl acetate (2×20 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to give the crude product. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-[4-[4-(2-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]phenyl]acetic acid (66 mg, 31%).
Reaction SMILES: Cl.C([NH:9][C@@H:10]([C:25]([NH:27][C@@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])=[O:26])[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])(OC(C)(C)C)=O.Cl.CCOC(C)=O.[C:43]1([CH:49]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:50](Cl)=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[C:15]([NH:14][CH2:13][CH2:12][CH2:11][C@H:10]([C:25]([NH:27][C@@H:28]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])=[O:26])[NH:9][C:50](=[O:51])[CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 23.2 %

Procedure:
Prepared according to the method described in Examples 2(b) and 2(c) above from (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-(1-phenylethyl)ornithine amide hydrochloride (5.9 g; 13 mmol; from step (a) above) EtOAc (30 mL) then HCl/EtOAc (100 mL), 3.5 hours reaction time for the deprotection, then CH2Cl2 (100 mL), diphenylacetyl chloride (2.9 g; 13 mmol) followed by pyridine (3.0 mL; 37 mmol; instead of DiPEA) over 1 min, overnight reaction time, diluted with CH2Cl2 (100 mL) for the work up procedure. The organic layer was partially concentrated at reduced pressure, upon which a precipitate formed, which was filtered to give 1.7 g (24%) of the sub-title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.OC1C=CC(CC(O)=O)=CC=1.[NH3:27]>>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[NH2:27]
Reactant: N
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Agent: O=C(O)Cc1ccc(O)cc1
Product: Nc1cnn(-c2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,5-Dichloro-2-phenyl-pyridazinone (2.41 g), 4-hydroxyphenyl-acetic acid (1.0 g) and 20% aqueous ammonia (20 ml) were heated to 100°-110° C. with stirring in a small autoclave for 4 hours. The reaction mixture was then cooled to room temperature, and the resulting precipitate of 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone was isolated by filtration, washed with water and dried. 1.86 g of pure 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone were obtained, m.p. 206°-207° C. The mother liquor and the washings contained 0.15 g of 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone. The total amount of 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone formed was thus 2.01 g (91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]2[CH2:23][CH2:22][Si:21](C3C=CC=CC=3)([CH2:24][CH2:25][CH2:26][CH2:27][F:28])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C@H:18]3[CH2:19][CH2:20][Si@H:21]([CH2:24][CH2:25][CH2:26][CH2:27][F:28])[CH2:22][CH2:23]3)[CH2:16][CH2:17]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)c(F)c1
Reactant: FCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](CBr)CC2)CC1
Product: FCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(F)c(F)c3)CC2)CC1

Procedure:
The general procedure of Example 39 was repeated using 3,4-difluorophenol and 4-(trans-4-bromomethylcyclohexyl)-1-phenyl-1-(4-fluorobutyl)-1-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]([NH:22][NH2:23])=[O:21]>CO>[NH2:17][C:16]1[N:22]([C:20]([O:19][CH3:18])=[O:21])[N:23]=[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=12
Reactant: CCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Reactant: COC(=O)NN
Solvent: CO
Product: CCCn1c(=O)c2c(N)n(C(=O)OC)nc2c2ccccc21
Yield: 54.3 %

Procedure:
In 60 ml of methanol were refluxed 2.00 g (8.1 mmol) of Compound b prepared in Example 2 and 1.10 g (12.2 mmol) of methoxycarbonylhydrazine for 6 hours. The reaction mixture was cooled to obtain 1.32 g (54%) of the titled compound as a colorless crystal.
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]([CH3:27])[C:24]([F:28])=[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.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[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:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([CH2:38][Cl:39])=[CH2:37])=[CH:30][CH:29]=3)[N:23]=[C:22]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[N:21]=2)=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([CH2:38][Cl:39])=[CH2:37])=[CH:30][CH:29]=3)[N:23]=[C:22]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[N:21]=2)=[CH:15][CH:14]=1
Reactant: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)NCC(C)(C)CN)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl(3-(4-((4-((4-((2-(chloromethyl)allyl)oxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (1 g) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum. The residue was diluted with EtOAc (200 mL), washed with 10% of NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated to give N-(3-amino-2,2-dimethylpropyl)-4-(4-(4-(2-(chloromethyl)allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (0.8 g).
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[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(S(C)(=O)=O)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 10.86 (br s, 1, NH), 8.65 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 8.02 (m, 4H), 7.78 (d, 1H, J=8.8 Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.1-7.3 (m, 3H), 3.07 (s, 3H), 2.41 (s, 3H). MS: m/z 465 (M+1).