Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:39]=[CH:38][C:9]([CH2:10][O:11][C:12]([C:14]2[N:19]3[C:20](=[O:31])[C@@H:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[C@H:18]3[S:17](=O)[CH2:16][C:15]=2N2CCCC2)=[O:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(O)(=O)C>C(COC)OC.[Ti](Cl)(Cl)(Cl)Cl>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]([C:14]2[N:19]3[C:20](=[O:31])[C@@H:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[C@H:18]3[S:17][CH2:16][CH:15]=2)=[O:13])=[CH:38][CH:39]=1)([O-:5])=[O:4]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N3CCCC3)CS(=O)[C@H]12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 36 h

Procedure:
To a mixture of 9.5 g (50 mmols) of titanium(IV) chloride and 5.67 g (150 mmols) of sodium borohydride in 150 ml of dimethoxy ethane is slowly added, at -20° C., a suspension of 10.86 g (20 mmols) of 7β-[2-(2-thienyl)-acetylamino]-3-pyrrolidino-3-cephem-4-carboxylic acid p-nitrobenzyl ester 1-oxide in 150 ml of ethylene glycol dimethyl ether, so that the temperature does not rise above -15° C. When the addition is complete, the reaction mixture is warmed to 0° C. and then a mixture of 50 ml of glacial acetic acid and 50 ml of ethylene glycol dimethyl ether is added dropwise. The reaction mixture is then stirred for 36 hours at room temperature. While cooling with ice, 200 ml of ice-water are cautiously added dropwise to the blue reaction solution. After extraction with three 150 ml portions of methylene chloride, the organic phase is dried over sodium sulfate and the solvent is removed by vacuum distillation, affording almost pure 7β-[2-(2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid p-nitrobenzyl ester as a foam.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[C:15]([F:20])[CH:14]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Br)cc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 10 parts of 3,4,5,6-tetrahydrophthalic anhydride in 100 parts of glacial acetic acid was treated in one portion with 11 parts of 4-bromo-2-fluoroaniline and was stirred for 30 minutes. The reaction mixture was refluxed for 16 hours and then poured over 200 parts ice. The resulting purple crystals were filtered and recrystallized from 100 parts methanol at -40°C to yield 13 parts of pink plates of 2-(4-bromo-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 102.0°-102.5°C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[NH3+:15][C@H:16]([C:25]1[NH2+:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][N:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23].CCN(CC)CC.[Cl-].Cl[S:45]([N:48]([CH3:54])[CH2:49][CH2:50][NH+:51]([CH3:53])[CH3:52])(=[O:47])=[O:46]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[CH3:52][NH+:51]([CH3:53])[CH2:50][CH2:49][N:48]([CH3:54])[S:45]([NH:15][C@H:16]([C:25]1[NH2+:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][N:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])(=[O:47])=[O:46]
Reactant: CC(=O)CCCCC[C@H]([NH3+])C1=NC=C(c2ccccc2)[NH2+]1
Reactant: CN(CC[NH+](C)C)S(=O)(=O)Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CCCCC[C@H](NS(=O)(=O)N(C)CC[NH+](C)C)C1=NC=C(c2ccccc2)[NH2+]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution Example 1, A3 and Et3N (4 eq.) in DCM was added crude C1 (1.2 eq). The mixture was stirred at RT for 16 hr. The mixture was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound C2 as a colourless oil. 1H NMR (300 MHz, DMSO-d6) δ: 8.18 (1H, br. s), 7.87 (1H, br. s), 7.83-7.71 (2H, m), 7.58-7.28 (3H, m), 4.64-4.45 (1H, m), 3.41-3.16 (4H, m), 2.79 (6H, s), 2.63 (3H, s), 2.39 (2H, t, J=6.8 Hz), 2.05 (3H, s), 1.98-1.78 (2H, m), 1.53-1.19 (6H, m). MS (ES) C22H35N5O3S requires: 449, found: 450 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>CO.O1CCOCC1>[ClH:28].[ClH:28].[N:11]1([C:15]2[CH:16]=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)c1cc(N2CCCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(6-Isopropyl-quinolin-8-yl)-[1,4]-diazepan-1-carboxylic acid tert-butyl ester (1.3 g, 1.0 equiv) was dissolved in MeOH (5 mL) and 1.0 M HCl in 1,4-dioxane (10 mL) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was concentrated to dryness to afford the title compound (1.2 g, 100%). MS (ES) m/z 270.1 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:18]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:35])[CH:27]=4)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.FC(F)O[C:40]1C=C(S(Cl)(=O)=O)C=C[CH:45]=1>>[CH2:40]([O:31][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][CH2:14][N:13]([S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:36])[CH:5]=4)(=[O:12])=[O:11])[C:18]=3[CH:19]=2)=[O:24])=[CH:27][C:28]=1[F:35])[CH3:45]
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(OC(F)F)c1)CCO2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(OC(F)F)c2)CCO3)cc1F

Procedure:
4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=521.2 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-difluoromethoxy-benzenesulfonyl chloride and yielded 4-{[4-(3-difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]12(C(=O)C3C[CH:11]1[CH2:12][CH2:13]3)[CH2:10][CH2:9][CH2:8][CH2:7]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:4]=[C:3]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:11]2[CH2:1][CH:2]1[CH2:13][CH2:12]2
Reactant: O=C1C2CCC(C2)C12CCCC2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1C2CCC(C2)C12CCCC2
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a suspension of (methyl)triphenylphosphonium bromide (17.6 g, 48.4 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (18.1 mL of 2.5 M solution in THF, 45 mmol) and the mixture was stirred 30 min. To this mixture was added spiro[bicyclo[2.2.1]heptane-2,1′-cyclopentan]-3-one (5.30 g, 32.3 mmol), and the reaction was stirred at ambient temperature for 18 h. Hexanes (200 mL) were added, and the mixture was filtered. The filtrate was concentrated, and the residue was purified on an 80 g silica gel column, eluting with hexanes, to obtain 3-methylenespiro[bicyclo[2.2.1]heptane-2,1′-cyclopentane] (4.80 g, 91.7%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:31]3[CH:30]=[N:29][C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[CH:33][CH:32]=3)=[CH:14][C:6]1=2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3Cl)CCN4)cn2)CC1
Yield: 50 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (94 mg) was coupled to 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a brown solid (50% yield). LCMS: m/z=468.97 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.33 (3H, s), 2.51 (4H, t, J=5.1 Hz), 3.48 (2H, m), 3.55 (4H, t, J=5.1 Hz), 3.64 (2H, t, J=4.7 Hz), 4.46 (2H, s), 5.20 (1H, bs), 6.52 (1H, d, J=1.5 Hz), 6.65 (1H, d, J=8.8 Hz), 7.19 (1H, dd, J=8.5, 2.4 Hz), 7.26 (1H, d, J=2.3 Hz), 7.33 (1H, d, J=8.3 Hz), 7.52 (1H, dd, J=8.6, 2.5 Hz), 7.62 (1H, d, J=1.5 Hz), 8.20 (1H, d, J=2.5 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].[NH:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[NH2:12].Cl>CCO>[NH2:8][C:7]1[N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:12]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: NNc1cccc(O)c1
Reactant: CC(C)(C#N)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C#N)c1cc(N)n(-c2cccc(O)c2)n1
Yield: 53 %

Procedure:
2,2-Dimethyl-3-oxo-pentanedinitrile (WO 2008/034008, which is incorporated herein by reference in its entirety, 353 mg, 2.80 mmol) and Intermediate 20a (387 mg, 2.80 mmol) were suspended in EtOH (10 mL) and concentrated HCl was added (711 μL, 8.53 mmol) and the reaction was refluxed for 90 min. The reaction was cooled, concentrated in vacuo and partitioned between H2O and EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo and the resulting oil was triturated with pentane/Et2O (9:1) to afford the title compound as a brown solid (363 mg, 53%). LCMS (Method 3): Rt 2.77 min, m/z 243.3 [MH+].
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][OH:23])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O[C:27]1[CH:31]=[CH:30][O:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CCOC(C)=O>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][O:23][C:27]5[CH:31]=[CH:30][O:29][N:28]=5)[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reaction time: 18 h
Yield: 85.4 %

Procedure:
3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (3.52 g, 10 mmol), 3-hydroxyisoxazole (893 mg, 10.05 mmol), and triphenylphosphine (3.03 g, 12 mmol) were dissolved by stirring in dry tetrahydrofuran (75 ml) under nitrogen. The mixture was cooled in an ice-bath, and diisopropylazodicarboxylate (2.33 g, 12 mmol) added dropwise over 10 minutes. The solution was stirred 18 hours, allowing the temperature to rise to ambient. The mixture was diluted with EtOAc (750 ml). the organic layer washed with water (3×500 ml), dried (magnesium sulfate) and evaporated. The residue was purified by MPLC on silica, eluting with a gradient between 0.25% and 1% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give product (3.58 g).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]4[C:19](=[C:29]([CH3:32])[C:30]#[N:31])[C:20]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=5[O:22][CH2:23][C:17]=4[CH:16]=3)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:35][O-:36].[Na+].O>CO>[CH:11]1([C:9]2[N:10]=[C:3]3[C:2]([O:36][CH3:35])=[N:7][CH:6]=[CH:5][N:4]3[C:8]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:13][CH2:12]1
Reactant: CC(C#N)=C1c2ccc(Cc3c(C4CC4)nc4c(Cl)nccn34)cc2COc2cc(F)ccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nccn2c(Cc3ccc4c(c3)COc3cc(F)ccc3/C4=C(\C)C#N)c(C3CC3)nc12
Temperature: 60 °C
Yield: 1 %

Procedure:
Using cyclopropanecarboxyaldehyde (0.586 mL, 7.74 mmol), 3-chloropyrazin-2-amine (739 mg, 5.7 mmol) and 2-(8-ethynyl-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.5 g, 5.18 mmol) obtained in Reference Example 9, and in the same manner as in Reference Example 8B, 2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile was obtained. Successively, the obtained 2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyrazin-3-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile was dissolved in methanol (1 mL), 28% sodium methoxide (0.3 mL, 0.425 mmol) was added, and the mixture was stirred with heating at 60° C. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 v/v) to give the title compound (25 mg, 1%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:1][C:2]1[C:3]([C:8]([O:10][CH2:8][CH2:3][CH2:2][CH2:7][CH2:6][CH3:5])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCBr
Reactant: O=C(O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOC(=O)c1ncccc1OCCCCCC
Temperature: 100 °C
Yield: 40.5 %

Procedure:
To a mixture of 2.80 g (20 mmol) of 3-hydroxypicolinic acid, 4.13 g (25 mmol) of n-hexyl bromide and 30 ml of N,N,-dimethylformamide was added 2.8 g (0.02 mmol) of anhydrous potassium carbonate, and the mixture was stirred under heating at 100° C. for 4.5 hours. After cooling, 60 ml of ice-water was added, and the mixture extracted with ethyl acetate. The solution was subjected to evaporation under a reduced pressure and the residue separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to obtain 2.60 g of a colorless oily substance (yield 40.5%).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].O>C(#N)C>[Si:24]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 12 g of 4-anilinophenol (64.7 mmol) in 200 mL of acetonitrile there are added, at ambient temperature, 6.7 g of imidazole (97.05 mmol) and 11.7 g of tert-butyl(chloro)dimethylsilane (77.64 mmol). The batch is stirred at 70° C. for 4 hours. The reaction mixture is then poured into water and extracted with ether. The organic phase is then dried over magnesium sulphate, then filtered and evaporated to dryness. The crude product thereby obtained is then purified by chromatography over silica gel (petroleum ether/dichloromethane gradient). The title product is obtained in the form of a powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=O)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29][NH2:30].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:29][NH:30][CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:22][CH3:23]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (5.0 g) is dissolved in 1,2-dichloroethane (20 ml) and thereto are added 3,5-bis-(trifluoromethyl)benzylamine (3.8 g), acetic acid (1.1 ml) and triacetoxy-sodium borohydride (4.0 g), and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=10:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (7.2 g). MS (m/z): 550 [M+H]+
Reaction SMILES: [I-].[Br:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH2:32]([O:35][C:36]1([CH3:65])[CH2:41][CH2:40][N:39]([C:42]2[N:47]3[N:48]=[C:49]([CH:51]=O)[CH:50]=[C:46]3[N:45]=[C:44]([CH3:53])[C:43]=2[C@H:54]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:38][CH2:37]1)[CH:33]=[CH2:34]>C1COCC1>[CH2:32]([O:35][C:36]1([CH3:65])[CH2:37][CH2:38][N:39]([C:42]2[N:47]3[N:48]=[C:49]([CH:51]=[CH:6][CH2:5][C:4]4[CH:26]=[CH:27][CH:28]=[CH:29][C:3]=4[Br:2])[CH:50]=[C:46]3[N:45]=[C:44]([CH3:53])[C:43]=2[C@H:54]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:40][CH2:41]1)[CH:33]=[CH2:34]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(C=O)nn23)CC1
Reactant: Brc1ccccc1CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(C=CCc4ccccc4Br)nn23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
To a suspension of (2-bromophenethyl)triphenylphosphonium iodide (0.121 g, 0.212 mmol) in THF (1 ml) at 0° C. was added sodium hydride (8.68 mg, 0.217 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to −78° C. and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.050 g, 0.106 mmol) dissolved in THF (1 ml) was added dropwise and the mixture was stirred at −78° C. for 1 h then warmed to room temperature and stirred 2 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 20 CV) to give the title compound (0.0386 g, 0.060 mmol, 57.0% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65-7.50 (m, 1H), 7.40-7.30 (m, 1H), 7.28-7.20 (m, 1H), 7.17-7.05 (m, 1H), 6.73-6.55 (m, 1H), 6.54-6.44 (m, 1H), 6.11-5.74 (m, 3H), 5.56-4.97 (m, 2H), 4.33-4.11 (m, 4H), 4.07-3.98 (m, 1H), 3.94 (d, J=4.4 Hz, 1H), 2.62 (s, 3H), 2.01-1.79 (m, 3H), 1.77-1.64 (m, 1H), 1.29-1.19 (m, 15H), (4 piperidine protons not visible in NMR). LCMS (M+H) calcd for C33H43BrN4O4: 640.24. found: 641.4.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=[O:10])[CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C.O>[N+:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([O:11][CH2:20][CH:19]=[CH2:18])=[O:10])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1csc([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1csc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
2-Nitro-4-thiophenecarboxylic acid (2.5 g, 14.45 mmol) was suspended in DMF (25 ml) in the presence of potassium carbonate (4 g, 28.9 mmol) at ambient temperature. Allyl bromide (5 ml, 57.8 mmol) was added to this solution and the mixture stirred at ambient temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate/petroleum ether as eluant (10:30) to give the title compound (2.45 g, 77%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].C[N:29](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([NH2:29])=[O:27])[CH2:22][N:23]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: O=C(O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a mixture of (2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (153 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (72 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (91 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=95:5), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (118 mg, yield: 77%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1)=[O:8].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[N:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[O:11]=[C:10]1[C:5]2[C:6](=[CH:12][C:2]([NH:1][C:23]([NH:22][C:15]3[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=3[Cl:13])=[O:24])=[CH:3][CH:4]=2)[C:7](=[O:8])[NH:9]1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: O=C=Nc1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2c(c1)C(=O)NC2=O)Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 4 h

Procedure:
5-Aminophthalimide (100 mg, 0.62 mmol) and 2,4,6-trichlorophenyl isocyanate (150.9 mg, 0.68 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[C:29]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:20])[S:16][CH:17]=2)[CH:7]=[N:6][CH:5]=1>[Li+].[OH-]>[CH:31]1([C:29]([C:23]2[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=2[NH:21][C:19](=[O:20])[NH:18][C:15]2[S:16][CH:17]=[C:13]([CH2:12][CH2:11][O:10][C:8]3[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=3)[C:3]([OH:36])=[O:2])[N:14]=2)=[O:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1cncc(OCCc2csc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)n2)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCOc3cncc(C(=O)O)c3)cs2)c(C(=O)C2CCCC2)c1
Yield: 93 %

Procedure:
5-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}ethoxy)nicotinic acid (23 mg, 95%) was prepared from 5-(2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}ethoxy)nicotinic acid methyl ester (0.025 g, 0.05 mmol) and 2.5M LiOH (20 ul) following the general procedure J.