Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.[OH-].[Na+].O>C(O)C>[F:25][C:2]([F:1])([F:24])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[N:4]=1
Reactant: CCOC(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Yield: 49.6 %

Procedure:
A mixture of ethyl {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetate (0.92 g, 2.61 mmol), sodium hydroxide (114 mg, 2.85 mmol), in ethanol (10 ml) and water (10 ml) was stirred at reflux for 1 hour. The reaction mix was allowed to cool and the ethanol was removed under reduced pressure and the residue was made acidic with 5N HCl, then extracted into dichloromethane. The organic layer was added to a 5 g pre-packed column and eluted from 0-100% ethyl acetate in petroleum ether to give the title compound as a pale yellow solid (0.42 g, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+].CO>CC(O)(CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCC(C)(C)O
Product: CC1(c2cccc(Br)c2)COCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of (RS)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (5.36 g, 17 mmol) in 2-methyl-2-butanol (100 ml) was treated in one portion with potassium tert-butylate (6.66 g, 58 mmol). Initially, the temperature rose to 30° C.; the reaction mixture was left to cool to room temperature and stirring was continued for one hour. For the workup, the reaction mixture was treated with methanol (50 ml), then evaporated at reduced pressure. The residue was purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent. 4.18 g (88%) of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one were obtained as a white solid. Mass (calculated) C11H12BrNO2 [270.128]; (found) [M+H]+=270 and [M+2+H]+=272.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=[C:7]([F:28])[C:6]=1[F:29])=[O:4].[OH-].[Na+]>O1CCCC1>[C:22]([SiH2:21][O:20][C:19]([CH3:27])([CH3:26])[C:16]1[CH:17]=[CH:18][C:13]([C:8]2[C:7]([F:28])=[C:6]([F:29])[C:5]([C:3]([OH:4])=[O:2])=[C:10]([F:11])[C:9]=2[F:12])=[CH:14][CH:15]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1c(F)c(F)c(-c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc2)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(-c2c(F)c(F)c(C(=O)O)c(F)c2F)cc1
Temperature: 10 °C
Yield: 88.5 %

Procedure:
To a solution of 4′-(tert-butyl-dimethyl-silanyloxymethyl)-2,3,5,6-tetrafluoro-biphenyl-4-carboxylic acid methyl ester (2.6 g, 6.0 mmol) in tetrahydrofuran (50 mL) was added an aq. solution of 5 N sodium hydroxide (20 mL). The reaction mixture was stirred and refluxed for 5 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated. The resulting residue was cooled to 10° C. and acidified with an aq. solution of 50% HCl. The formed precipitate was filtered, washed thoroughly with water and dried to get colorless solid (2.2 g, 88.0%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH2:32]Cl)=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1)#[N:21].C(N(C(C)C)CC)(C)C>C(#N)C>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:27]2[C:31]([CH2:32][N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:16]=[CH:17][CH:18]=[C:3]([CH3:2])[CH:4]=4)([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11]3)=[CH:30][N:29]=[CH:28]2)=[CH:34][CH:35]=1)#[N:21]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: Cc1cccc(CC2(C(N)=O)CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(CC2(C(N)=O)CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1

Procedure:
A solution of 4-(3-methylbenzyl)isonipecotamide hydrochloride salt (134 mg, 0.5 mmol), 1-(4-cyanobenzyl)-5-chloromethyl-imidazole hydrochloride salt (134 mg, 0.5 mmol; Example 52, Step D), and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in chloroform saturated with ammonia gas. After collection and concentration of appropriate fractions, the residue was triturated with anhydrous diethyl ether. The white solid precipitated was filtered to provide the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: CC(C)c1ccc(C(=O)O)cc1Oc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C)c(Oc3ccccc3)c2)c(O)n1
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
To a solution of 4-isopropyl-3-phenoxybenzoic acid (100 mg, 0.39 mmol) in dichloromethane (20 mL) were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol), N-hydroxy benzotriazole (68 mg, 0.50 mmol) and triethylamine (175 mg, 1.73 mmol). The resultant reaction mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (61 mg, 0.40 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl-3-phenoxy benzamide (50 mg, 32.8%) as a white solid. LRMS (M+H+) m/z: calcd 391.19. found 391 HPLC purity (214 nm): 90.4%. 1H NMR (300 MHz, DMSO) δ 7.58 (m, 1H), 7.55 (m, 1H), 7.33 (m, 3H), 7.07 (m, 1H), 6.89 (m, 2H), 6.07 (s, 1H), 4.44 (s, 2H), 3.31 (m, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 1.24 (d, J=9 Hz, 6H).
Reaction SMILES: O.O.O.O.O.O.O.[S:8]([O-:11])([O-:10])=[O:9].[Na+:12].[Na+].Br[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1>O1CCOCC1.O>[O:18]1[CH2:19][CH2:20][CH:16]([CH2:15][S:8]([O-:11])(=[O:10])=[O:9])[CH2:17]1.[Na+:12]
Reactant: O=S([O-])[O-]
Reactant: BrCC1CCOC1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)([O-])CC1CCOC1
Reaction time: 18 h
Yield: 57 %

Procedure:
Sodium sulfite heptahydrate (6.10 g) was added to a solution of 3-(bromomethyl)tetrahydrofuran (2.0 g) [see Preparation 9] in 1,4-dioxane (9 ml) and water (9 ml). The reaction mixture was then heated under reflux and stirred for 18 hours, cooled and the solvent removed under reduced pressure. The resulting solid was dissolved in water and concentrated to a low volume. The solid formed was then collected to afford sodium tetrahydrofuran-3-ylmethanesulfonate (1.30 g) as a white solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23](ON3C(=O)CCC3=O)=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>O.C1COCC1>[C:23]([N:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4])([O:22][CH2:21][CH:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[C:20]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:24]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC[C@H]1CO
Reaction time: 1 h
Yield: 74 %

Procedure:
L-prolinol (Compound 1) (0.61 g, 6.0 mmol) was dissolved in 70 ml of pure water, thus preparing an L-prolinol aqueous solution. N-(9-Fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (2.0 g, 6.0 mmol) was dissolved in 10 ml of THF. This THF solution was added to the L-prolinol aqueous solution, and this was stirred for 1 hour so as to react the L-prolinol and the Fmoc-OSu. The reaction solution was separated into a liquid fraction and a precipitate fraction. These fractions respectively were subjected to extraction with ethyl acetate, and organic layers respectively were collected therefrom. The thus-obtained organic layers were mixed together, and anhydrous sodium sulfate was added thereto to absorb moisture (hereinafter, this process is referred to as a “drying” process). The organic layers were filtered, and the filtrate obtained was vacuum concentrated. The residual substance obtained was purified by silica gel column chromatography (the eluent: hexane:ethyl acetate=1:1). Thus, Compound 2 was obtained (1.4 g, yield: 74%). The result of NMR analysis with respect to this compound is shown below.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[CH3:15][N+:16]([O-:18])=[O:17].CC(=O)OCC>CC(O)=O.O>[CH3:13][C:4]1([CH3:14])[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8](/[CH:11]=[CH:15]/[N+:16]([O-:18])=[O:17])[CH:9]=[CH:10][C:5]1=2
Reactant: CC1(C)OB(O)c2cc(C=O)ccc21
Reactant: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)OB(O)c2cc(/C=C/[N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (1.14 g, 6 mmol) and NH4OAc (47 mg, 0.6 mmol) in AcOH (10 mL) at rt was added CH3NO2 (10 mL). The reaction mixture was stirred at 100° C. for 3 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel by elution with PE:EA (2:1 to 1:1) to give (E)-3,3-dimethyl-6-(2-nitrovinyl)benzo[c][1,2]oxaborol-1(3H)-ol as a yellow solid (750 mg, yield 53%). 1F1 NMR (500 MHz, CDCl3) δ 9.18 (s, 1H), 8.18 (s, 2H), 8.01 (s, 1 H), 7.99 (d, J=8.0 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 1.46 (s, 6H) ppm; MS: m/z=234.1 (M+1, ESI+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:39]=[CH:38][C:19]3[N:20]([CH3:37])[C:21]([C:23]4[N:31]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:39]=[CH:38][C:19]3[N:20]([CH3:37])[C:21]([C:23]4[N:31]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1c(-c2cc3cccnc3n2CC(F)(F)F)nc2cc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(-c2cc3cccnc3n2CC(F)(F)F)nc2cc(C(=O)N3CCC[C@@H](N)C3)ccc21
Reaction time: 0.75 h
Yield: 85.2 %

Procedure:
To a stirred solution of (R)-tert-butyl(1-(1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (1.9336 g, 3.47 mmol) in dichloromethane (DCM) (5.5 ml) was added TFA (5.05 ml, 66.0 mmol) dropwise. The reaction mixture was stirred for 45 min. The mixture was concentrated in vacuo, dissolved in methanol and purified by SPE on a pre-conditioned sulfonic acid (SCX) 70 g cartridge. The column was washed with methanol (5 CV) and the product was eluted with a 2M Ammonia in methanol solution (4 CV). The appropriate fractions were combined and the solvent was evaporated in vacuo to give a crude product that was purified by preparative HPLC (MDAP Method E). Appropriate fractions were combined and concentrated in vacuo to yield the title compound (1.35 g)
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:49][C:50]([F:64])([F:63])[C:51]1[CH:52]=[C:53]([CH:60]=[CH:61][CH:62]=1)[O:54][CH:55]1[CH2:59][CH2:58][NH:57][CH2:56]1>CN(C=O)C.O>[O:27]=[C:25]([N:57]1[CH2:58][CH2:59][CH:55]([O:54][C:53]2[CH:60]=[CH:61][CH:62]=[C:51]([C:50]([F:49])([F:64])[F:63])[CH:52]=2)[CH2:56]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: FC(F)(F)c1cccc(OC2CCNC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)C1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 61.9 %

Procedure:
DIPEA (167.7 mg, 1.29 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (106 mg, 0.43 mmol) in DMF (4 mL) followed by HOBt (70.13 mg, 0.52 mmol) and EDCI (99.5 mg, 0.52 mmol). After 2 minutes of stirring, 3-(3-trifluoromethyl-phenoxy)-pyrrolidine (100 mg, 0.43 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the precipitate was collected to afford 122 mg (61.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[3-(3-trifluoromethyl-phenoxy)-pyrrolidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 459.16, 96.52%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.05 (bs, 1H), 7.8 (db, 2H), 7.7-7.6 (m, 7H), 7.05 (bs, 1H), 5.4 (s, 1H), 5.3 (s, 1H), 4.1 (m, 2H), 3.9 (m, 1H), 3.8-3.6 (m, 3H), 3.4 (m, 1H), 2.3-2.0 (m, 2H).
Reaction SMILES: [C:1]([NH2:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].N1CCCC1.I[C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>[Cu]I>[C:1]([NH2:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:29]#[C:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: C#CCCCCCCCCC(N)=O
Reactant: CCCCCCCCC#CC#CCCCCCC#CI
Agent: [Cu]I
Solvent: C1CCNC1
Product: CCCCCCCCC#CC#CCCCCCC#CC#CCCCCCCCCC(N)=O
Reaction time: 48 h

Procedure:
CuI (0.126 g, 0.66 mmol) and 10-undecynoic acid amide (0.29 g, 1.59 mmol) were added to a flask and inerted with nitrogen. Pyrollidine (5 mL) was then added. In a separate flask 1-Iodo-nonadeca-1,8,10-triyne (0.5 g, 1.3 mmol) was mixed with pyrollidine (5 mL) and subsequently added slowly to the amide solution. The reaction mix was left in darkness under nitrogen for 48 hours, then quenched with aqueous 1M NH4Cl (10 mL), and worked up with CH2Cl2 and 1 M HCl. The organic was dried over anhydrous MgSO4. Organic products were concentrated by rotary evaporation, although polymer formed, decreasing yield. Hexanes trituration removed unreacted 1-Iodo-nonadeca-1,8,10-triyne. Desired product was obtained by several crystallizations from hexanes/ethyl acetate, again under dark conditions. All handling of the solid was done under red light. Final product triaconta-10,12,19,21-tetraynoic acid amide was made up of white crystals (0.377 g, 0.86 mmol) and was stored frozen (liquid nitrogen) in methylene chloride. 65% yield; 1H NMR (CDCl3) δ: 5.31 (s, 2H, NH2), 2.22-2.26 (m, 10H, CH2—C≡C & CH2—CO), 1.58-1.66 (quin, 2H, J=7, CH2—C—CO), 1.45-1.56 (m, 8H, CH2—C—C≡C), 1.28-1.4 (m, 20H, C—CH2—C), 0.86-0.91 (t, 3H, CH3); 13C NMR (CDCl3) δ 175.69, 77.98, 77.84, 77.34, 65.69, 69.45, 65.37, 57.68, 53.63, 38.37, 38.35, 33.80, 32.97, 32.92, 32.03, 29.34, 29.27, 29.07, 28.94, 28.55, 28.47, 28.26, 28.26, 28.06, 27.17, 25.67, 22.86, 19.39, 19.32 14.30. MS (ESI) [M+H]+calc. 436.3574 found 436.3560.
Reaction SMILES: CN1C(NC(=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:24]=[C:23]3[C:19](/[C:20](=[CH:26]/O)/[C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=CC(C)=N1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C1COCC1>[CH3:23][NH:22][C:21](=[O:25])[C:12]1[CH:13]=[CH:14][CH:9]=[C:10]([S:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20](=[CH:26][NH:43][C:40]4[CH:41]=[CH:42][C:37]([N:34]5[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]5)=[CH:38][CH:39]=4)[C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)[CH:11]=1
Reactant: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)/C3=C\O)n(C)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(Sc2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 68 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A 1 mL vial was charged with N-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-{3-[1-hydroxy-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-6-ylsulfanyl}-benzamide (as prepared below; 55 mg, 0.135 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (25.8 mg, 0.138 mmol), and THF (1 mL). This reaction mixture was stirred for 24 h at 68° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was re-suspended in EtOAc (5 mL) and extracted with H2O (˜5 mL). The organic layer was concentrated in vacuo and the residue was chromatographed via flash silica gel chromatography (gradient of 1-10% MeOH in CHCl3) afforded the title compound in 35% yield (27 mg, 0.047 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([NH2:18])=[O:17]>ClCCl>[C:16]([C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([NH:12][C:8]([C:7]2[C:6]([Cl:11])=[N:5][CH:4]=[N:3][C:2]=2[Cl:1])=[O:9])[CH:14]=1)(=[O:17])[NH2:18]
Reactant: COc1ccc(C(N)=O)cc1N
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COc1ccc(C(N)=O)cc1NC(=O)c1c(Cl)ncnc1Cl
Reaction time: 1 h
Yield: 66 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (430 mg, 2.03 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (3 ml) and TEA (283 μl, 2.03 mmol) was added. To this solution, 3-amino-4-methoxybenzamide (338 mg, 2.03 mmol) dissolved in 3 ml dichloromethane was added dropwise and the mixture was stirred for 60 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (366 mg, 93% purity, 66% yield) was used in the next synthetic step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][CH2:10][CH:9]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:8]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:10][CH:9]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[C:8]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(NC1CNc2ccccc2N(c2ccccc2)C1=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)N1CC(NC(=O)OCc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 84.7 %

Procedure:
1-Phenyl-2-oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (300 mg) was dissolved in methylene chloride (15 ml), isobutyryl chloride (107 mg), pyridine (79 mg) and 4-(N,N-dimethyl)aminopyridine (1 mg) were added, the mixture was refluxed for 2 hours. The reaction mixture was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 300 mg of the title compound (Yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.P(Br)(Br)[Br:16]>C(Cl)Cl>[Br:16][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COc1ccc(CO)c(C(F)(F)F)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1ccc(CBr)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of (4-methoxy-2-trifluoromethyl-phenyl)-methanol (1.04 g, 5 mmol) in DCM (20 mL) was treated at 0° C. with phosphorous tribromide (1.64 g, 6 mmol). The reaction mixture was stirred for 10 minutes at 0° C., 1 h at room temperature. The solvent was evaporated in vacuo to yield a crude oil which was purified via flash chromatography (10% DCM in hexane) to yield the title compound as an oil (1.36 g, 100%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@@H:29]1[C:41]([OH:43])=[O:42])=[O:27])([CH3:24])([CH3:23])[CH3:22].CI>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][C:29]1([CH3:1])[C:41]([OH:43])=[O:42])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)C[C@@H]1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a cooled (−78° C.) solution of diisopropylamine (0.032 mol) in dry THF (15 mL), n-BuLi (0.030 mol) was added dropwise under argon atmosphere, and the reaction was stirred for 30 min at −78° C., then for one hour at −20° C. The resulting LDA solution was transferred to the solution of the known compound (R)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (CAS: 54631-81-1, e.g. Tetrahedron, 42(21), 6039-45; 1986) (3.5 g, 0.011 mol) in THF (15 mL) at −78° C., and the mixture was stirred for 30 minutes at −78° C., then at 0° C. for one hour. The reaction mixture was once again cooled to −78° C. and methyl iodide (0.82 mL, 0.013 mol) was added to it over 10 min and stirred the reaction mixture was stirred at 0° C. then at rt for one hour. After completion of the reaction by TLC, the reaction mixture was quenched with 1N HCl (20 mL) and extracted with DCM. The organic layer was concentrated under reduced pressure to give a crude material, which was purified through column chromatography (10-20% ethyl acetate:hexane, basic alumina, diameter of column—2.5 cm, height of alumina—approx. 7 inch) to afford the desired (rac)-4-benzyloxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 800 mg (22%) as a white solid.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:9]=1)=[O:7])[CH3:4]>C(O)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[C:12]([Br:1])=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1Br
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Bromine (15 ml, 294 mmol) was added in one portion to a cooled (ice/water bath) stirred solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (26.6 g, 73.6 mmol) in acetic acid (300 ml). After 45 minutes, the reaction was concentrated in vacuo, the solids slurried in diethyl ether (100 ml), filtered and dried in vacuo to afford the title compound (I-1a) as a light-yellow colored solid, 29.6 g.