Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[CH:22]([CH:24]([CH:30]=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=O>CCO.CC(O)=O>[C:20]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[N:5][N:6]2[CH:30]=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:1][C:2]=12)#[N:21]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: CCOC(=O)C(C=O)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (276 mg, 1.0 mmol) in EtOH (10 mL) was added ethyl 2-formyl-3-oxopropanoate (144 mg, 1.0 mmol) and HOAc (5 drops). After stirring at RT for 16 hr, the mixture was filtered. The cake was washed with H2O (10 mL×2) and dried to afford 250 mg (65%) of ethyl 3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate as a yellow solid. MS (ESI) m/e [M+1]+ 384.9.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:38])[CH2:28][CH2:29][S:30][CH2:31][C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:38])[CH2:28][CH2:29][S:30][CH2:31][C:32]1[N:33]=[C:34]([NH:37][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:15]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)[CH:8]=2)[S:35][CH:36]=1)[CH3:25]
Reactant: CCOC(=O)CCSCc1csc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Product: CCOC(=O)CCSCc1csc(NC(=O)c2cc(Oc3ccc(F)cc3)cc(O[C@@H](C)COC)c2)n1

Procedure:
3-{2-[3-(4-Fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-ylmethylsulfanyl}-propionic acid ethyl ester was prepared from 3-(4-fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and 3-(2-amino-thiazol-4-ylmethylsulfanyl)-propionic acid ethyl ester following general procedure A.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:17]=[N:16][N:15]=2)=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O>CC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:28][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A mixture of compound D (8.0 g), N-bromosuccinimide (4.53 g) and azo(bisisobutyronitrile) (73 mg) in methyl chloroform (50 ml) was heated at reflux for 4 hours. The mixture was cooled to ambient temperature, washed with water (3×50 ml), and the suspended solid collected by filtration to give 5-(4'-bromomethylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (E) (7.3 g), m.p. 192°-195° C.; NMR (CDCl3): 4.4(2H, s), 6.52(2H, d), 6.85(2H, d), 7.07(2H, d), 7.4(1H, d), 7.7(2H, m), 7.9(1H, d).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][CH3:18])=[CH:9][CH:8]=1)[CH3:2].Cl[CH:21]([C:23]1[C:24]([CH3:39])=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[CH3:22].[Na+].[I-].C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]([CH3:18])[CH:21]([C:23]2[C:24]([CH3:39])=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC)c2ccccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc(N(C)C(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12
Temperature: 40 °C
Reaction time: 20 h

Procedure:
0.095 g (0.37 mmol) of the above prepared (4-methylamino-naphthalen-1-yloxy)-acetic acid ethyl ester and 0.220 g of [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see below 1G], 2.0 eq.) were treated in 2.8 ml of DMSO with 0.110 g (1 eq.) of NaI and 0.168 g (1.5 eq.) of DBU. After stirring for 20 h at 40° C., the reaction mixture was poured onto crashed ice/KHSO4, extracted twice with AcOEt, washed with water and brine, and dried over sodium sulfate. Evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15), afforded 0.055 g of the title compound as light brown oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].Cl.Cl.NC1C=CC(N2CCC[C@@H](C(N3CCCC3)=O)C2)=NC=1N.NC1N=C(N2CCC[C@@H](C(N3CCOCC3)=O)C2)C=CC=1[N+]([O-])=O.[CH:72]1([C:75]2[N:80]=[C:79]([C:81](=N)OCC)[CH:78]=[N:77][CH:76]=2)[CH2:74][CH2:73]1>>[CH:72]1([C:75]2[N:80]=[C:79]([C:81]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:20][CH2:21][O:22][CH2:23][CH2:24]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH:78]=[N:77][CH:76]=2)[CH2:74][CH2:73]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)nc1N
Reactant: CCOC(=N)c1cncc(C2CC2)n1
Agent: Cl
Agent: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Nc1nc(N2CCC[C@@H](C(=O)N3CCOCC3)C2)ccc1[N+](=O)[O-]
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4cncc(C5CC5)n4)[nH]c3n2)C1)N1CCOCC1

Procedure:
The title compound was prepared by a method analogous to the one used for Example 95, but using (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(morpholino)methanone dihydrochloride (synthesized by hydrogenation analogous to the one used for Intermediate 1, starting from Intermediate 40) and Intermediate 30. 1H NMR (300 MHz, DMSO-d6) δ 1.06 (dd, 2H), 1.20-1.33 (m, 3H), 1.54-1.74 (m, 3H), 1.80-1.93 (m, 1H), 2.19-2.33 (m, 2H), 2.79 (br s, 1H), 2.87-3.09 (m, 3H), 3.55 (m, 5H), 4.30-4.53 (m, 2H), 6.88 (d, 1H), 7.86 (d, 1H), 8.61 (s, 1H), 9.06 (s, 1H), 13.05 (s, 1H)
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].C(B(CC)[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)C>COCCOC.O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=1
Reactant: CCB(CC)c1cccnc1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc2ccccc2nc1-c1cccnc1
Temperature: 90 °C
Yield: 70.3 %

Procedure:
A mixture of 2-chloroquinoline-3-carbaldehyde (5.0 g, 26.1 mmol), Na2CO3 (4.15 g, 39.1 mmol) and diethyl(3-pyridyl)borane (4.22 g, 28.7 mmol) in DME (100 mL) and water (30 mL) was degassed by bubbling nitrogen gas through it for 5 minutes. Tetrakis-(triphenylphosphine)palladium(0) (0.30 g, 0.261 mmol) was added and the mixture was heated at 90° C. for 5 h. The mixture was allowed to cool to room temperature. The resultant precipitate was filtered off and washed with water (5×50 mL) and diethyl ether (5×50 mL) to give the title compound (4.3 g, 70%) as a pale green solid. LCMS (ES+) 235 (M+H)+, RT 1.53 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][C:8]3[CH:13]=[N:14][C:15]([CH3:17])=[N:16][C:7]=3[C:6]=2[CH:18]=1.CN(C)[CH:21]=[N:22][CH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:10]([CH2:9][C:8]4[CH:13]=[N:14][C:15]([CH3:17])=[N:16][C:7]=4[C:6]=2[CH:18]=1)=[C:23]([C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1)[N:22]=[CH:21]3
Reactant: Cc1cc(CN=CN(C)C)no1
Reactant: Cc1ncc2c(n1)-c1cc(Br)ccc1NC(=O)C2
Product: Cc1ncc2c(n1)-c1cc(Br)ccc1-n1cnc(-c3cc(C)on3)c1C2

Procedure:
From 10-bromo-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-one according to scheme 1, step 7 using N,N-dimethyl-N′-(5-methyl-isoxazol-3-ylmethyl)-formamidine instead of (E)-(dimethylaminomethyleneamino)-acetic acid ethyl ester. Clear gum, m/z (ISP) 407/409 (MH)
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:11](Cl)=[O:12].[CH2:18]([O:20][C:21]([C@:23]1([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:28]([NH2:29])[CH2:27][C@@H:26]2[C@H:24]1[C@@:25]2([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:18]([O:20][C:21]([C@:23]1([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@H:28]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:8]([Cl:7])[CH:9]=2)[CH2:27][C@@H:26]2[C@H:24]1[C@@:25]2([F:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])[CH3:19]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NC(=O)c3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
7.3 μL of pyridine and 14 mg of 3,4-dichlorobenzoyl chloride were added to 17 mg of (1R,2R,3R,5R,6R)-3-amino-2-t-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.17 mL of chloroform, and the mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: chloroform-ethanol=100:1), thereby yielding 21 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzoylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].CO>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:22][C:14]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=2[F:12])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COC(=O)c1cc(Cl)ccn1
Solvent: Clc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
4-Chloropyridine-2-carboxylic acid methyl ester (30 g) and 2-fluoro-4-nitrophenol (41.2 g) were dissolved in chlorobenzene (24 ml), followed by stirring under a nitrogen atmosphere at 120° C. for 4 hr. The reaction mixture was allowed to cool down to room temperature, methanol (100 ml) was added, and stirred for 30 min. The solvent was removed under reduced pressure, then the resultant residue was partitioned between ethyl acetate (300 ml) and a 1N aqueous solution of sodium hydroxide (150 ml). The separated organic layer was washed with a 1N aqueous solution of sodium hydroxide (100 ml) and brine (150 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, ethanol (200 ml) was added to the resultant residue, followed by stirring for 30 min. The solid was collected by filtration and the filtrate was purified by silica gel column chromatography (YMC, SIL-60-400/230W, eluent; heptane:ethyl acetate=1:1). Fractions containing the target compound were concentrated under reduced pressure, the resultant solid was combined to the solid above to provide 4-(2-fluoro-4-nitrophenoxy)pyridine-2-carboxylic acid methyl ester as a pale brown solid (20.0 g, 40.0%).
Reaction SMILES: C(#N)C.[C:4]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[N:20]=2)=[CH:15]\C(O)=O)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[Br:28]N1C(=O)CCC1=O>C(N(CC)CC)C>[Br:28]/[CH:15]=[C:14](/[C:19]1[N:20]=[C:21]([O:26][CH3:27])[C:22]([Cl:25])=[CH:23][CH:24]=1)\[C:11]1[CH:12]=[CH:13][C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:9][CH:10]=1
Reactant: COc1nc(/C(=C/C(=O)O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc(/C(=C/Br)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
A 97% acetonitrile solution (52 mL) containing triethylamine (26 μL) was added to (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-enoic acid (1.3 g). N-bromosuccinimide (806 mg) was added thereto and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure from the reaction solution. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to give the title compound as a colorless powder (363 mg, 25%).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([O:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 73.2 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), N-(4-hydroxyphenyl)acetamide (85 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 mL), and stirred for 20 minutes at 180° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, and washed with H2O. The precipitate was triturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 81 (48 mg, 74% yield) as a tan solid. LC-MS (M+H=346, obsd.=346). 1H NMR (400 MHz, d6-DMSO): δ 11.92 (s, 1H), 10.04 (s, 1H), 8.69 (dd, 1H), 8.50 (dd, 1H), 8.30 (d, 1H), 8.05 (d, 1H), 7.68 (m, 2H), 7.29 (dd, 1H), 7.16 (m, 3H), 2.08 (s, 3H).
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].C(N(CC)CC)C.ClC(OCC)=O.[C:25]1([CH2:31][O:32][C:33]2[C:34]([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:53]=3)=[C:35]([CH2:47][CH2:48][NH2:49])[CH:36]=[CH:37][C:38]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:25]1([CH2:31][O:32][C:33]2[C:34]([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH2:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[CH:53]=3)=[C:35]([CH2:47][CH2:48][NH:49][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:36]=[CH:37][C:38]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1CCc1cccc(OCc2ccccc2)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCCC(=O)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1CCc1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of monomethyladipate (0.74 ml) and triethylamine (0.69 ml) in dry dichloromethane (50 ml) was stirred at 0° during the dropwise addition of a solution of ethyl chloroformate (0.48 ml) in dry dichloromethane (20 ml). The mixture was stirred under an atmosphere of nitrogen at 0° for 30 minutes and a solution of 3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy]phenyl]ethyl]benzeneethanamine (2.70 g) in dry dichloromethane (50 ml) was then added. The mixture was stirred at 20° for 18 hours.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O.CN(C)C=O>COC(C)(C)C>[C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reaction time: 3 h
Yield: 100 %

Procedure:
3-Acetoxy-2-methylbenzoic acid was slurried in methyl-t-butyl ether (MTBE) and treated with 1.2 equivalents of thionyl chloride and catalytic dimethylformamide. After three hours at ambient temperatures, the reaction was complete, giving a brown solution. Solvent (MTBE) was removed by vacuum distillation. Residual thionyl chloride was removed by addition of toluene followed by vacuum distillation. The resulting 3-acetoxy-2-methylbenzoyl chloride was isolated either directly as an oil or by crystallization from two volumes of heptane at <10° C. Product was obtained in >100% yield when isolated as an oil and 82-85% yield when crystallized from heptane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]([OH:28])=O)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]([N:32]([CH3:33])[CH3:31])=[O:28])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(=O)O)n3)n2)ccc(C#N)c1Cl
Reactant: CNC
Agent: Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(=O)N(C)C)n3)n2)ccc(C#N)c1Cl
Yield: 4.18 %

Procedure:
(S)—N4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-N2,N2-dimethylthiazole-2,4-dicarboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylic acid (0.2 g, 0.340 mmol) and dimethylamine hydrochloride (0.023 g, 0.283 mmol). The product was purified by Flash-chromatography and triturated using diethyl ether, respectively. Yield 4.18%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.51 (s, 3H), 3.09 (s, 3H), 3.24 (s, 3H), 4.23 (dd, 1H), 4.45 (dd, 1H), 4.62 (m, 1H), 6.41 (d, 1H), 7.48 (d, 1H), 7.51 (d, 1H), 7.54 (dd, 1H), 7.85 (d, 1H), 8.27 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([N:10](CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:15][CH2:16][C:17]([NH2:1])=[O:18].[Cl:15][CH2:16][C:17]([NH2:10])=[O:18].[NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCl
Agent: C1CNCCNC1
Solvent: ClC(Cl)Cl
Product: NC(=O)CCl
Temperature: -30 °C
Reaction time: 8 h

Procedure:
Homopiperazine (10 g; 100 mmol) was dissolved in chloroform (150 mL) and triethylamine (28 mL; 200 mmol) was added to the mixture. The solution was cooled to -30° C. under nitrogen and chloroacetyl chloride (17 mL, 213 mmol) was added over a period of 1 hour. The solution was stirred at -30° C. for 1 hour, at 0° C. for 2 hour and at ambient temperature overnight. The solution was washed with water (4×50 mL), dried over anhydrous MgSO4, filtered and concentrated. The oily residue was purified by column chromatography on silica gel (5% methanol in chloroform) to yield the title product as an oil which solidified on prolonged standing (10.3 g; 41%). 1H NMR (CDCl3): 4.04 (m, 4 H), 3.62 (m, 8 H), and 1.94 (m, 2 H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]1=[O:14])C.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][C:9]1[CH:10]=[C:11]([CH3:12])[N:6]([CH2:5][C:4]([NH:17][NH2:18])=[O:3])[C:7](=[O:14])[CH:8]=1
Reactant: CCOC(=O)Cn1c(C)cc(C)cc1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C)n(CC(=O)NN)c(=O)c1

Procedure:
As described for example 112a, (4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (Shusherina, N. P.; Slavyanova, O. V.; Petrova, L. K.; Levina, R. Ya. Zhurnal Organicheskoi Khimii (1972), 8(2), 387-9) in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 120 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the title compound was obtained as a white solid (yield. 90%). MS: m/e=218.2 [M+Na]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>[OH-].[Na+].C(OCC)C>[CH3:13][C:12]1[CH:14]=[CH:15][C:9]([S:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: NCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
Glycine (1 g, 13.32 mmol) was dissolved in 1N NaOH (aq.) and a solution of tosyl chloride (2.62 g, 13.72 mmol) in diethyl ether (15 ml) was added portion wise with stirring over 10 min. The resulting mixture was allowed to stir at room temperature for 3 h. The ethereal layer was separated and the aqueous layer treated with 2N HCl solution until acidified to pH 5. After cooling the resulting solution to 0° C., the product began to precipitate from the solution. The solid was collected by filtration and the mother liquor placed in a fridge overnight causing more of the desired product to precipitate. The solid was again collected by filtration and the combined collected solid was dried under high vacuum affording 9 as a white powder (613 mg, 21%). δH (400 MHz, MeOD) 2.41 (3H, s, CH3), 3.66 (2H, s, CH2), 7.35 (2H, d, J=8 Hz, ArH), 7.73 (2H, d, J=8 Hz, ArH); δc (100.6 MHz, MeOD) 20.3, 43.6, 127.0, 129.5, 137.6, 143.6, 171.0; MS (ES+) 246.8 (100%, [M+H2O]+); MS (ES−) 227.9 (100%, [M−H]−); HRMS [M−H]− requires 228.03360, found 228.03364.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25].II>O>[C:24]([CH:23]([S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1])[CH2:22][C:21]([OH:28])=[O:27])([OH:26])=[O:25]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: II
Solvent: O
Product: N[C@@H](CCC(=O)N[C@@H](CSC(CC(=O)O)C(=O)O)C(=O)NCC(=O)O)C(=O)O
Reaction time: 12 h
Yield: 71 %

Procedure:
In 150 ml of water are dissolved 9.2 g of glutathione and 5.0 g of maleic acid and the solution is allowed to stand at room temperature for 12 hours. One or 2 drops of the reaction mixture is taken as a test sample and one drop of 0.01 N-iodine test solution (Japanese Pharmacopoeia XII) is added. After confirming that the consumption of iodine has ceased, 6.6 g of copper acetate (monohydrate) is added to the reaction mixture and dissolved and any precipitate is filtered off. The filtrate is concentrated to about 70 ml and diluted with ethanol and the precipitated blue copper salt is recovered by filtration and recrystallized from water-ethanol. This copper salt is dissolved in 200 ml of water and hydrogen sulfide is then bubbled through the solution to precipitate the copper sulfide which is then filtered off. The filtrate is concentrated under reduced pressure and diluted with ethanol and the resulting white crystals are collected by filtration, washed with ethanol and recrystallized from water-ethanol. Thus is obtained about 9 g of the title compound as white amorphous crystals (hygroscopic).