Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][NH:35][NH2:36]>>[CH3:34][NH:35][NH:36][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([CH2:17][S:14]([CH:13]=[C:11]2[CH2:12][N:9]([CH:8]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:10]2)(=[O:16])=[O:15])[CH:19]=1
Reactant: CNN
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: CNNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0141 cm3 of methylhydrazine. 42 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid N′methylhydrazide are thus obtained in the form of a pale yellow foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2.96 (s, 3H), 3.18 (broad s, 3H), 3.83 (mt, 2H), 4.22 (mt, 2H), 4.80 (broad s, 2H), from 7.35 to 7.65 (mt, 12H)].
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]3[N:24]=[C:25]([NH:27][C:28](C)([CH3:31])[CH2:29]O)[S:26][C:22]=3[CH2:21][CH2:20][O:19][C:18]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]3[N:24]=[C:25]([N:27]4[C:28]([CH3:29])([CH3:31])[CH2:7][O:6][C:5]4=[O:11])[S:26][C:22]=3[CH2:21][CH2:20][O:19][C:18]=2[CH:33]=1
Reactant: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 3 h

Procedure:
Triphosgene (148 mg, 0.500 mmol) was added to a mixture of 185 mg (0.500 mmol) of 2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-ol and 0.522 ml (3.00 mmol) of diisopropylethylamine in 7.0 ml of methylene chloride. The reaction mixture was stirred for 3 hours and concentrated in vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid. The organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuum. Yield 194 mg (98%). MS (ESI+): 396.3
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][S:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=3[N:3]12.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]2[S:10][CH2:9][C:4]3=[N:5][NH:6][C:7](=[O:8])[CH:2]([CH3:1])[N:3]3[C:12]=2[CH:13]=1
Reactant: CC1C(=O)NN=C2CSc3ccc([N+](=O)[O-])cc3N21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CC1C(=O)NN=C2CSc3ccc(N)cc3N21
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]thiazino[3,4-c][1,2,4]triazin-2(1H)-one (0.308 g, 1.11 mmol) in MeOH (25 mL) and THF (25 mL) was added powdered zinc (0.724 g, 11.1 mmol) and NH4Cl (0.592 g, 11.1 mmol) and the mixture was heated at reflux for 16 h. After cooling to ambient temperature, the mixture was filtered to give crude 9-amino-1-methyl-3,5-dihydrobenzo[5,6][1,4]thiazino[3,4-c][1,2,4]triazin-2(1H)-one (100%), which was used in the next step directly without further purification. TLC (eluting with 50% EtOAc/PE) Rf=0.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:13]#[N:14].[K+]>CO>[C:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 22 °C

Procedure:
To a solution of 5.71 g (24.9 mmol) of methyl 3-bromomethylbenzoate in 36 mL of methanol was added 2.11 g (32.4 mmol) of potassium cyanide. The mixture was refluxed for about 16 h, cooled to 22° C. and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give methyl 3-(cyanomethyl)benzoate.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(=O)CCl
Product: COc1cc(NCCCc2ccc(OCCN(C)C)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 29.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronap hthalen-2-yl ester (19 mg) and 2-chloro-N,N-dimethylacetamide (8.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21][N:20]=1>Br.O>[CH3:25][C:23]1[N:22]=[CH:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[CH:24]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(N)ncn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2nccn2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (3.43 ml, 22.1 mmol) in concentrated hydrobromic acid (1.1 ml) and water (1.1 ml) was heated at reflux under nitrogen for 2 h, then poured into ethanol (57 ml). The solution was neutralised to pH 7 with solid sodium hydrogen carbonate, then filtered. To the filtrate was added 4-amino-6-methylpyrimidine (1.0063 g, 9.22 mmol) and the mixture was stirred at room temperature for 30 min then at 60° C. for 19 h. After allowing to cool, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2CO2) to give 0.5071 g (41%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 2.54 (3H, s), 7.33 (1H, s), 7.59 (1H, s), 7.62 (1H, d, J 1.2 Hz), 8.96 (1H, s); MS (ES+) m/z 134 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:34])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][NH:23][C:24]2[S:25][C:26]3[CH:32]=[C:31]([O:33][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[CH:30]=[CH:29][C:27]=3[N:28]=2)=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nc3ccc(O)cc3s2)cc1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2nc(NCc3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)sc2c1
Reaction time: 4 h
Yield: 37.5 %

Procedure:
To a suspension of compound 129 (1.00 g, 2.04 mmol) in THF (6.8 mL) at room temperature under N2 atmosphere were successively added N,N-dimethylethanolamine (225 μL, 2.24 mmol) and triphenylphosphine (696 mg, 2.65 mmol) followed by diisopropyl azodicarboxylate (550 μL, 2.65 mmol). Heat was evolved and the mixture turned dark red. It was stirred for 4 h, THF was removed in vacuo and the dark residue was partitioned between EtOAc and H2O. Organic phase was collected and extracted with HCl 1N. Acidic extract was separated and neutralized with saturated aqueous NaHCO3 under vigorous stirring. A white precipitate was formed which was collected by filtration to afford the title compound 133 (430 mg, 37% yield). 1H NMR: (acetone-d6) δ(ppm): 7.99 (d, J=8.4 Hz, 2H), 7.70 (dd, J=8.0, 2.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.56 (d, J=1.6 Hz, 1H), 7.33 (d, J=9.0 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.19 (quint.d, J=7.8, 2.4 Hz, 2H), 6.87 (dd, J=8.8, 2.5 Hz, 1H), 4.80 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 2.67 (t, J=5.7 Hz, 2H), 2.27 (s, 6H), 1.48 (s, 9H). m/z: 562.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](O)=[O:11])=[CH:4][C:3]=1[CH3:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(/C=C/C(=O)O)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(/C=C/CO)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.5 %

Procedure:
A mixture of trans-3-(4-fluoro-3-methylphenyl)prop-2-enoic acid (6.18 g) and oxalyl chloride (3.72 mL) in dichloromethane (40 mL) containing N,N-dimethylformamide (60 μL) is stirred at room temperature for three hours, concentrated under reduced pressure and redissolved in tetrahydrofurane (50 mL). The solution is maintained at a temperature below −8° C. during the addition of a suspension of sodium borohydride (2.9 g) in N,N-dimethylformamide (15 mL). The mixture is stirred for one hour at a temperature close to −12° C., hydrolysed by the successive addition of water (10 mL) and 1N hydrochloric acid and extracted with ethyl acetate. The organic layers are pooled, washed with water, dired over magnesium sulfate, concentrated under reduced pressure and purified by chromatography over silica gel, with heptane/ethyl acetate 3/1 as eluant, to give 710 mg of trans-3-(4-fluoro-3-methylphenyl)prop-2-en-1-ol as a colorless oil used without further purification.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:19]([O:23][C:24](=[O:39])[NH:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[NH:38])[NH:36]O)=[CH:31][N:30]=2)[CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24](=[O:39])[NH:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:36]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:6][N:38]=3)=[CH:31][N:30]=2)[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=N)NO)cn2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3noc(C4CC4)n3)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
An 8-mL vial was charged with cyclopropanecarboxylic acid (78.5 μL, 0.99 mmol) and DMF (1.0 mL). Carbonyldiimidazole (176 mg, 1.09 mmol) was added to the vial at room temperature. The clear reaction mixture was stirred for 2 h and then added to another 8-mL vial containing {1-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (430 mg, 1.47 mmol) in 1.0 mL of DMF. The resulting pale yellow reaction mixture was stirred at room temperature for 30 min and then heated at 100° C. for 16 h. The clear pale orange reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organics were washed with of water (2×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated to a crude oil. The crude oil was purified via normal phase flash chromatography on silica gel, eluting with 0-35% EtOAc/hexanes, to give {1-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (86 mg, 26%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10](=[O:13])[CH2:11]Br)([CH3:8])([CH3:7])[CH3:6]>ClCCl>[C:5]([O:9][C:10](=[O:13])[CH2:11][NH:4][CH2:1][CH:2]=[CH2:3])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CCN
Solvent: ClCCl
Product: C=CCNCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Allylamine (10 mL, 0.13 mol) was cooled to 0° C., a solution of bromoacetic acid tert-butyl ester (1.0 mL, 6.7 mmol) in dichloromethane (10 ml) was slowly added. After stirring at 0° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The obtained solution was concentrated under reduced pressure to give the title compound as a yellow liquid (1.15 g, 6.7 mmol, 99%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH2:18][CH:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][CH:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH2:18]2)[CH2:32][CH2:31]1
Reactant: O=CCCC1CC(c2cccc(Oc3ccccc3)c2)=NO1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccccc1N1CCN(CCCC2CC(c3cccc(Oc4ccccc4)c3)=NO2)CC1
Yield: 69.6 %

Procedure:
3-[3-(3-Phenoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (38.0 mg, 0.122 mmol), 1-(2-fluorophenyl)piperazine (20.0 mg, 0.111 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (70.5 mg, 0.333 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 35.5 mg (70.1 %) of the target compound was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[C:11]1([CH2:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[CH2:17]([NH:18][C:5]1[N:4]([CH3:9])[C:3](=[O:10])[C:2]([Br:1])=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cn1c(NCc2ccccc2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (Example 143, Step B, 0.100 g, 0.448 mmol), phenylmethanamine (0.064 ml, 0.582 mmol) and NaHCO3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer was washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.130 g, 99%) as a pale yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (t, 1H), 7.90 (s, 1H), 7.32 (s, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 4.57 (d, 2H), 3.39 (s, 3H). LRMS (ESI pos) m/e 294, 296 (M+, Br pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][N:20]3[C:24](=[O:25])[CH2:23][O:22][C:21]3=[O:26])[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[NH3:27]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:26])[O:22][CH2:23][C:24]([NH2:27])=[O:25])[CH2:16][CH2:17]1)[CH:6]=[CH:5]2
Reactant: O=C1COC(=O)N1CCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Reactant: N
Solvent: CO
Product: NC(=O)COC(=O)NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 3 (step 3.4). Starting with 1.28 g (3.42 mmol) of 3-{2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 10.3, and 22.10 ml (154.08 mmol) of a solution (7M) of aqueous ammonia in methanol, and after crystallization from ethanol, 0.64 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([NH:13][CH2:14][C:15]2([OH:28])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>ClCCl.C(=O)(O)[O-].[Na+]>[Si:1]([O:8][CH2:9][C:10]1([N:13]([CH2:14][C:15]2([OH:28])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[C:40](=[O:41])[CH2:39][Cl:38])[CH2:11][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNC2(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CN(C(=O)CCl)C2(CO[Si](C)(C)C(C)(C)C)CC2)CC1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirring solution of tert-butyl 4-(((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)amino)methyl)-4-hydroxypiperidine-1-carboxylate (1.688 mmol) and N,N-diisopropylethylamine (4.22 mmol) in anhydrous dichloromethane (30 mL) cooled to 0° C. was added neat chloroacetyl chloride (2.53 mmol). After 30 min, the reaction was diluted with saturated aq sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and were evaporated onto silica. Purification of the solid by flash chromatography (30% ethyl acetate in hexanes) afforded the title product (742 mg, 85% yield) as a light orange oil. MS(ES)+ m/e 491.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[OH:20])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.[CH3:40][O-:41].[Na+]>CCOC(C)=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([O:41][CH3:40])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[O-]
Reactant: Cn1cncc1C(O)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)c1ncccn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1nc2ccc(C(O)(c3ncccn3)c3cncn3C)cc2c(Cl)c1-c1ccccc1

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (156 mg, 0.337 mmol, Example 55), toluene (2 mL), and sodium methoxide (365 mg, 6.75 mmol) were combined in a round bottom flask equipped with a stirbar and condenser under an N2 atmosphere. The contents were heated to reflux and refluxed overnight. The reaction was cooled and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI): mass calcd. for C25H20ClN5O2, 457.1; m/z found, 458.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 8.81 (d, J=4.9 Hz, 2H), 8.48 (d, J=1.8 Hz, 1H), 7.92-7.81 (m, 2H), 7.54-7.39 (m, 4H), 7.36-7.28 (m, 3H), 6.55 (s, 1H), 6.15 (s, 1H), 3.98 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:19](B1OC(C)(C)C(C)(C)O1)=[CH2:20].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:17][CH:16]([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[N:6]=[N:7][C:2]([CH:19]=[CH2:20])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: FC(F)Oc1ccc(Nc2ccc(Cl)nn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ccc(Nc2ccc(OC(F)F)cc2)nn1
Temperature: 80 °C
Yield: 61.9 %

Procedure:
To a solution of 6-chloro-N-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (0.2 g, 0.736 mmol) in dioxane and water mixture were added vinylboronic acid pinacol ester (0.146 mL, 1.104 mmol), and K2CO3 (0.305 g, 2.209 mmol). The mixture was flushed for 15 min with nitrogen. PdCl2 (dppf)-CH2Cl2 adduct (0.060 g, 0.074 mmol) was then added and the reaction mixture heated at 80° C. for 18 h. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate and purified by flash chromatography on silica gel using ethyl acetate in hexane to give N-(4-(difluoromethoxy)phenyl)-6-vinylpyridazin-3-amine as a white solid (0.12 g, 59%). 1HNMR 400 MHz, DMSO-d6: δ ppm 5.47 (d, J=1.20 Hz, 1H), 6.06 (dd, J=0.80, 23.80 Hz, 1H), 6.84-7.38 (m, 5H), 7.75-7.82 (m, 3H), 9.42 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:23][C@H:24]([C:30]([OH:32])=O)[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1.[NH2:33][CH:34]([C:45]#[N:46])[CH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[Cl:44]>>[Cl:44][C:37]1[CH:38]=[C:39]([C:40]#[N:41])[CH:42]=[CH:43][C:36]=1[CH2:35][CH:34]([NH:33][C:30](=[O:32])[C@@H:24]([NH:23][C@@H:18]([C:15]1[CH:14]=[CH:13][C:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:17][CH:16]=1)[C:19]([F:21])([F:20])[F:22])[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:45]#[N:46]
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)O
Reactant: N#Cc1ccc(CC(N)C#N)c(Cl)c1
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)NC(C#N)Cc1ccc(C#N)cc1Cl

Procedure:
(S)-2-[(S)-1-(2′-Chloro-4′-methanesulfonyl-biphenyl-4-yl)-2,2,2-trifluoro-ethylamino]-4-fluoro-4-methyl-pentanoic acid [2-(2-chloro-4-cyano-phenyl)-1-cyano-ethyl]-amide was prepared from N-{(1S)-1-[2′-chloro-4′-(methylsulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucine and 4-(2-amino-2-cyanoethyl)-3-chlorobenzonitrile by following procedures as in step 4 of Example 2.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:9]=2[S:8](=[O:22])(=[O:21])[CH:7]=1)C.[OH-].[Li+].Cl>CO>[CH3:20][S:17]([NH:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:7][S:8](=[O:21])(=[O:22])[C:9]=2[CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (0.245 g, 0.680 mmol) in methanol (15 mL) was cooled to 0° C. in an ice-water bath and treated with 2.0 M aqueous lithium hydroxide solution (1.7 mL, 3.40 mmol). The reaction mixture was allowed to warm to 25° C. and stirred for 1 h. The reaction was poured into 0.5 M aqueous hydrochloric acid solution (50 mL) on ice, extracted with ethyl acetate (3×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give an orange solid. The crude solid was triturated with diethyl ether to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (0.175 g, 0.526 mmol, 77%) as a light orange solid. LC-MS (ESI) calcd for C11H12N2O6S2 332.4, found 333.3 [M+H+].