Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)#[N:18].[OH-].[Na+].C(O)C>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[C:17]#[N:18])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(SCc2ccccc2C#N)cc(C(C)(C)C)c1O
Yield: 18.9 %

Procedure:
A solution of 2.00 g (8.39 mmole) of 2,6-di-t-butyl-4-mercaptophenol, 1.65 g (8.39 mmole) of o-cyanobenzyl bromide, 5 ml of 1.68N sodium hydroxide and 75 ml of ethanol was heated at reflux for 48 hours. The reaction mixture was poured into water and was extracted with diethyl ether. The ether extract was washed with water, dried with magnesium sulfate and evaporated to give the crude product as an oil. The oil was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and hexane, followed by recrystallization from hexane to give 0.56 g of white 2,6-di-t-butyl-4-[(2-cyanophenyl) methylthio]phenol, m.p. 79°-82° C. Analysis: Calculated for C22H27NOS: %C, 74.7; %H, 7.7; %N, 4.0; Found: %C, 74.6; %H, 7.9; %N 3.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[C:25]([Si:29]([O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([N:39]=[C:40]=[O:41])[CH2:35][CH2:34]1)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].CCN(CC)CC>ClCCCl>[C:25]([Si:29]([CH3:31])([CH3:30])[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:40](=[O:41])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]2[N:10]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[CH2:35][CH2:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2cccc(Cl)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)N(c2cccc(Cl)c2)c2c3ccccc3nn2-c2ccc(Cl)cc2)CC1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine (example 19.1) was reacted with trans-tert-butyl-(4-isocyanato-cyclohexyloxy)-dimethyl-silane (Dermatakis, Apostolos; Kabat, Marek Michal; Luk, Kin-Chun; Rossman, Pamela Loreen; So, Sung-Sau. PCT Int. Appl. (2004), WO 2004041822 A1) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 6 days under reflux conditions to give the title compound as brown solid. MS: m/e=611.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[C:13]([O:26][CH3:27])[CH:14]=[C:15]([CH2:24][NH2:25])[C:16]=1[NH:17]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:40]1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:29]([CH2:28][C:12]1[C:11]2[S:10][C:9]3[C:18](=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:8]=3[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:17]([C:39](=[O:46])[CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:16]=2[C:15]([CH2:24][NH2:25])=[CH:14][C:13]=1[O:26][CH3:27])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCCC(=O)O1
Reactant: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C(=O)CCCC(=O)O
Temperature: 0 °C
Yield: 71.1 %

Procedure:
A mixture of 360 mg (0.67 mmol) of benzyl (6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-4-yl)-acetate, 91.7 mg (0.80 mmol) of glutaric anhydride and 63.7 mg (0.80 mmol) of pyridine in 5 ml of toluene was treated with 10 mg of N,N-dimethylaminopyridine. The mixture was heated to 110° under argon for 48 hours and then poured into ice-water, whereupon the mixture was acidified with 1N hydrochloric acid and exhaustively extracted with methylene chloride. The organic phase was dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with chloroform/methanol (9:1), whereupon 310 mg (71%) of 5-(4-benzyloxycarbonylmethyl-6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-10yl)-5-oxo-pentanoic acid were obtained as a white solid of m.p. 65°-68°.
Reaction SMILES: [I:1][C:2]#[C:3][C:4]([CH3:7])([OH:6])[CH3:5].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH2:13][N:14]=[N+:15]=[N-:16]>>[I:1][C:2]1[N:14]([CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[C:10]([C:9]([F:8])([F:21])[F:20])[CH:11]=2)[N:15]=[N:16][C:3]=1[C:4]([OH:6])([CH3:7])[CH3:5]
Reactant: CC(C)(O)C#CI
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Product: CC(C)(O)c1nnn(Cc2cccc(C(F)(F)F)c2)c1I

Procedure:
Synthesized from 4-iodo-2-methylbut-3-yn-2-ol and 3-trifluoromethyl-benzylazide using general procedure; 3.82 g, 9.30 mmol, 93%; mp=77-80° C.; IR (υ[cm−1]) 3385, 2981, 2938, 1326, 1170, 1120, 1074, 763, 699; 1H NMR (600 MHz, CDCl3) δ=7.58-7.57 (m, 2H), 7.48-7.45 (m, 1H), 7.42-7.41 (m, 1H), 5.62 (s, 2H), 1.66 (s, 6H); 13C NMR (151 MHz, CDCl3) δ=156.4, 135.4, 131.5 (q, J=33.2), 131.4, 129.8, 125.7 (q, J=3.7), 125.1 (q, J=3.8), 123.9 (q, J=272.4), 74.2, 69.7, 53.8, 30.1; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C13H14F3IN3O, 412.0128; found 412.0126.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][NH:17][CH3:18].[BH4-].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:17]([CH3:18])[CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CNC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.8 %

Procedure:
A mixture of 1-(4-(diethoxymethyl)benzaldehyde (2.08 g, 10 mmol) and dimethylamine (33% aqueous solution, 2.74 g, 20 mmol) in methanol (20 mL) was stirred at room temperature for 40 mins. The mixture was cooled to 0° C., sodium borohydride (0.57 g, 15 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 1-(4-(diethoxymethyl)phenyl)-N,N,-dimethylmethanamine (1.8 g) as a light yellow oil which was used in the next step without further purification. MS (ESI) m/z: 237(M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cccc2[N+](=O)[O-])CC1
Yield: 74.4 %

Procedure:
To a stirred solution of 1.01 g (5.0 mmol) of 1-chloro-2,6-dinitrobenzene and 0.93 g (5.0 mmol) of 1-tert-butyloxycarbonylpiperazine in acetonitrile (5 mL) was added 1.38 g (10 mmol) of K2CO3. The mixture was heated to reflux for 48 h. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and 20 mL of H2O. The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% EtOAc/hexanes) provided 1.31 g (85%) of 4-(2,6-dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester TLC (silica, 20% EtOAc/hexanes): Rf=0.35. 1H NMR (400 MHz, CDCl3): 7.75 (d, J=8.2 Hz, 2H), 7.25 (t, J=8.2 Hz, 1H), 3.30 (m, 4H), 2.95 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([O:31]C)=[O:30])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].O>CO>[C:1]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)c1c[nH]c2cc(C(=O)O)ccc12
Temperature: 25 °C
Yield: 82.2 %

Procedure:
Methyl 3-(n-octadecanoyl)indole-6-carboxylate (35.2 g) in methanol (1620 ml), containing sodium hydroxide (32 g) and water (49 ml), was stirred and refluxed for 2 hours. The solution was cooled to room temperature and the solid was collected. The solid was suspended in water (500 ml) and aqueous hydrochloric acid (20 ml, of strength 36% w/v) was added to the suspension with rapid stirring. The solid was collected and was recrystallised from glacial acetic acid to give 3-(n-octadecanoyl)indole-6-carboxylic acid (28 g), in the form of a white solid, m.p. 268°-270° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.[C:23](O)(=[O:25])[CH3:24].O>C(OC(=O)C)(=O)C>[C:23]([O:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][C:3]=1/[CH:4]=[CH:12]/[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: CSc1ccc(O)c(C=O)c1
Reactant: COC(=O)c1ccc(C)nc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2cc(SC)ccc2OC(C)=O)nc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 71.2 %

Procedure:
2-hydroxy-5-methylsulfanylbenzaldehyde (5.05 g, 30 mmol) was dissolved in acetic anhydride (8 mL). Methyl 6-methylnicotinate (4.54 g, 30 mmol) and acetic acid (1.7 mL, 30 mmol) were added. The mixture was heated to 120° C. and stirred for 18 hours. The mixture was allowed to cool to room temperature before being poured into water (200 mL). The aqueous mixture was extracted with ethyl acetate (200 mL). The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford a brown solid. This material was triturated with ethanol to give 6-[E-2-(-2-acetoxy-5-methylsulfanylphenyl)-vinyl]-nicotinic acid, methyl ester as a colourless solid (7.33 g, 71%) δH (300 MHz, DMSO-d6) 9.06 (1 H, d), 8.28 (1 H, dd), 7.77−7.68 (3 H, m), 7.50 (1 H, d), 7.27 (1 H, d), 7.15 (1 H, d), 3.86 (3 H, s), 2.55 (3 H, s), and 2.36 (3 H, s); m/z (ESI+) 344 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:42]1([C:48](=[O:73])[CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH2:68])[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:58][CH:57]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C>[N:42]1([C:48](=[O:73])[CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH:68][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:58][CH:57]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)N1CCOCC1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-morpholin-4-yl-2-oxo-ethyl ester (54 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (35 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H33N5O6, 536.24. found 536.2.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11](Cl)=[O:12].Cl.[CH2:23]([NH:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([N:26]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:24][CH3:25])=[O:12]
Reactant: CCCNC(C)C
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
Triethylamine (27.89 mL, 200 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-propyl-N-iso-propylamine hydrochloride (~92 mmol) in toluene (100 mL). The reaction was stirred overnight at ambient temperature, then was partitioned between ethyl acetate and dilute citric acid. The organic phase was washed with brine, dried (MgSO4), and concentrated to afford 2.50 g of the title compound as a waxy amber solid, an 80% yield.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[CH:13][C:12]=3[CH:16]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[Li]CCCC.CCCCCC.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:14]1[O:15][C:11]2[CH:10]=[CH:9][C:8]([C:3]3([CH2:1][CH3:2])[O:4][CH2:5][CH2:6][O:7]3)=[CH:16][C:12]=2[CH:13]=1
Reactant: CCC1(c2ccc3occc3c2)OCCO1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1(c2ccc3oc(Cl)cc3c2)OCCO1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 64.2 %

Procedure:
To a stirred solution of 5-(2-ethyl-1,3-dioxolan-2-yl)benzofuran (350 mg, 1.0 eq) in 20 mL anhydrous THF was added 2.5 M n-BuLi solution in hexane (1.6 mL, 2.4 eq) dropwise at 0° C., and the mixture was stirred at 0° C. for 50 min under nitrogen. A solution of hexachloroethane (915 mg, 2.4 eq) in 10 mL anhydrous THF was added dropwise. The reaction was stirred at rt for 1 h, quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (260 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=0.4 Hz, 1H), 7.37-7.38 (m, 2H), 6.57 (s, 1H), 4.01-4.05 (m, 2H), 3.77-3.80 (m, 2H), 1.94 (q, J=7.6 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1>CN(C=O)C.CCOC(C)=O>[CH3:32][C:27]1[CH:28]=[C:29]([CH3:31])[N:30]=[C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3]3)[CH2:6]2)[N:26]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N2CC3CN(c4nc(C)cc(C)n4)CC3C2)c(-n2nccn2)c1
Temperature: 120 °C
Yield: 104.3 %

Procedure:
To (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (185 mg, 0.4 mmol) in DMF (2.2 mL) was added 2-chloro-4,6-dimethylpyrimidine (61 mg, 0.4 mmol). The flask was heated to 120° C. for 18 h. The flask was allowed to cool to rt, diluted with EtOAc and washed with H2O. The aq was back-extracted with EtOAc (1×). The combined organics were washed with brine and dried (Na2SO4) to give an oil. Purification via silica gel (15-75% EtOAc in hexanes) gave 175 mg (97%) of the title compound. MS (ESI) mass calcd. C22H25N7O2, 419.49; m/z found 420.2 [M+H]+. 1H NMR (CDCl3): 7.73 (s, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 6.29 (s, 1H), 3.93-3.80 (m, 5H), 3.72-3.63 (m, 2H), 3.58 (dd, J=11.6, 5.2 Hz, 1H), 3.46 (dd, J=11.6, 4.3 Hz, 1H), 3.39-3.28 (m, 1H), 3.05-2.84 (m, 3H), 2.33 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc(OCCCCl)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxybenzophenone (0.99 g), potassium carbonate (3.45 g) and 1-bromo-3-chloropropane (2.5 mL) in N,N-dimethylformamide (7.5 mL) affords 1.4 g of 4-(3-chloropropoxy)benzophenone as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:6][C:7](=[O:11])[C:8]=1OC)=[O:5])#[N:2].O.[NH2:13][NH2:14]>C(O)(C)C>[C:1]([C:3]1[C:4]([NH:6][C:7](=[O:11])[C:8]=1[NH:13][NH2:14])=[O:5])#[N:2]
Reactant: COC1=C(C#N)C(=O)NC1=O
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: N#CC1=C(NN)C(=O)NC1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
50 parts of 2-cyano-3-methoxymaleimide are introduced into a solution of 16.5 parts of hydrazine hydrate in 300 parts by volume of isopropanol, while cooling with ice, the reaction mixture is then stirred at room temperature for half an hour, and the red precipitate is filtered off under suction, washed with isopropanol and dried. 47 PG,6 parts (94% of theory) of 2-cyano-3-hydrazinomaleimide of melting point >350° C. are obtained. IR (KBr): 3120, 2200, 1670 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[C:6]([OH:12])[CH:5]=1.[CH3:14]OS(OC)(=O)=O.[OH-].[Na+].OS(O)(=O)=O>O>[OH:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:14])[C:7]=1[OH:11])[C:3]([O:2][CH3:1])=[O:13]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47 %

Procedure:
To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na2B4O7 (50 g) in water (1000 mL) was added Me2SO4 (120 mL) and aqueous NaOH solution (25%, 200 mL) successively at room temperature. The mixture was stirred at room temperature for 6 h before it was cooled to 0° C. The mixture was acidified to pH˜2 by adding conc. H2SO4 and then filtered. The filtrate was extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[H-].[Na+].Cl[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].O>CN(C=O)C>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: O=Cc1ccc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cccc1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (14.27 g) in DMF (143 mL) was added sodium hydride (60% dispersion in mineral oil, 6.6 g) at 0° C., and the mixture was stirred under argon atmosphere at 0° C. for 2 hr. To the reaction mixture was added a solution of (2-(chloromethoxy)ethyl)(trimethyl)silane (27.5 g) in DMF (20 mL), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (30 g).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12](C(O)=O)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C[C:67](N(C)C)=[O:68]>O.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:67]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:68])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution (10 mL) of 4-(cyclohexyl{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methoxy)benzoic acid (0.43 g) synthesized in Example 300 (1) in dimethylacetamide were added triethylamine (0.14 mL), ethyl 3-aminopropanoate hydrochloride (0.16 g), N-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.29 g) and 1-hydroxybenzotriazole monohydrate (0.23 g) at room temperature, and the mixture was stirred at 60° C. for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate and purified by silica gel chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a methyl ester form of the title compound (0.10 g). This was dissolved in ethanol (2 mL), 1N sodium hydroxide (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.5 mL) was added to the residue to give the title compound (25.4 mg, 5%) as an amorphous form.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].Br[CH2:23][CH2:24][CH2:25][C:26]#[N:27]>CN(C)C=O>[C:26]([CH2:25][CH2:24][CH2:23][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:27]
Reactant: N#CCCCBr
Reactant: [H][H]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCC#N)(C(=O)OCC)c1ccccc1
Temperature: 65 °C
Yield: 79.1 %

Procedure:
A 50% mineral oil dispersion containing 16.8 g (0.7 mol) of sodium hydride was placed in a 3-liter, three-necked, round-bottom flask and washed free of oil with 500 ml of dry hexane. To this was added 1.2 liters of dry dimethylformamide (DMF) and 165.4 g (0.7 mol) of diethyl phenylmalonate (Aldrich Chemical Co., Milwaukee, Wis.). After hydrogen ceased to be evolved (3.5 hours), 104.2 g (0.7 mol) of 4-bromobutyronitrile (Aldrich Chemical Co.) was added, and the reaction heated at 65° C. overnight. The solvent was removed under reduced pressure, and the residue suspended in 1 liter of ethyl acetate. It was filtered, the filtrate reevaporated, and the residue evaporatively distilled at 170° C./0.1 mm to give 168 g (79% yield) of the diester (15) as a yellow liquid.