Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[NH2:6].C=O.[C:23]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:23][NH:6][C:5]1[CH:7]=[CH:8][C:9]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:3]([CH3:2])[CH:4]=1
Reactant: [BH3-]C#N
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CNc1ccc(N2C(=O)c3ccccc3C2=O)c(C)c1

Procedure:
To a stirred solution of 1.4 g of the product aniline of Example 31 and 2.5 ml of 37% aqueous formaldehyde in 19 ml of acetonitrile was added in portions 0.62 g of sodium cyanoborohydride. After twenty minutes the solution was adjusted to pH 7 with glacial acetic acid and stirred for another hour. Ice was added, acetonitrile was removed in vacuo, and the mixture was partitioned between water and dichloromethane. The organic layer was dried over potassium carbonate, filtered, and concentrated to an oil which was chromatographed on a silica gel column using dichloromethane as eluent. Fractions containing the title compound were concentrated to give a solid, m.p. 159°-161°. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: C[Si]([N-:5][Si](C)(C)C)(C)C.[Li+].Cl[CH:12]([B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)[CH2:13][CH2:14][CH3:15].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>O1CCCC1>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH2:13]([CH:12]([B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)[NH2:5])[CH2:14][CH3:15]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCC(Cl)B1OC(C)(C)C(C)(C)O1
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCC(N)B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.2 %

Procedure:
1.7 ml (1.7 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise to a solution of 0.37 g (1.69 mmol) of 2-[1(RS)-chlorobutyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 ml of tetrahydrofuran under nitrogen at -78° C. The solution was then stirred overnight at room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 0.39 ml (5.1 mmol) of trifluoroacetic acid was added and the solution was stirred at 0° C. for 30 minutes. The solution was evaporated and the residue was co-evaporated with toluene to give 0.62 g of α-(RS)-propyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine trifluoroacetate as a brown oil which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:6][C:7]1(C)[CH2:12][CH:11]2[CH2:13][CH:8]1C=C2.[CH3:15][C:16]1[CH2:20]C=C[CH:17]=1>>[CH3:6][C:7]1[CH2:12][CH:11]=[CH:13][CH:8]=1.[CH:5]1[CH2:4][CH:3]=[CH:2][CH:1]=1.[CH3:17][C:16](=[CH2:15])[CH3:20]
Reactant: CC1(C)CC2C=CC1C2
Agent: C1=CCC=C1
Agent: CC1=CC=CC1
Product: C=C(C)C

Procedure:
In the same manner as in Example 2, a Diels-Alder reaction was carried out on isobutylene and cyclopentadiene in order to synthesize 5,5-dimethyl-2-norbornene, and the latter was then reacted with methylcyclopentadiene to produce a 1:1:1 adduct of methylcyclopentadiene, cyclopentadiene and isobutylene. That is to say, 225 g of isobutylene and 260 g of cyclopentadiene were placed in a 1000-ml autoclave, and heating was gradually accomplished so that its temperature might become 25° to 120° C. and a reaction was performed at 120° C. for 8 hours, so that 118 g of 5,5-dimethyl-2-norbornene were obtained. Then, 115 g of the latter compound were similarly reacted with 201 g of methylcyclopentadiene at 120° C. for 10 hours. Then, 97 g of a fraction having a boiling point 97° C./1 mmHg were obtained. According to the measurement by a mass spectrometer, it was found that a molecular weight of the fraction was 202. Further, IR analysis indicated that characteristic absorptions of olefins appeared at 3020 cm-1 and 1670 cm-1. From these results, it was elucidated that the fraction was the 1:1 adduct of 5,5-dimethyl-2-norbornene and methylcyclopentadiene, i.e., the 1:1:1 adduct of methylcyclopentadiene, cyclopentadiene and isobutylene.
Reaction SMILES: BrC[C:3]1[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:17]([Cl:27])[CH:16]=[CH:15][C:4]=1[C:5]([O:7][Si](C(C)(C)C)(C)C)=[O:6].COC(=O)[C@H](CS)NC(=O)[C@H](CO)NC(OC(C)(C)C)=O.N12CCCN=C1CCCCC2.C(O)(=O)C>C(Cl)Cl>[Si:20]([O:19][C:18]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:27])[C:5]([OH:7])=[O:6])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)c1ccc(Cl)c(O[Si](C)(C)C(C)(C)C)c1CBr
Agent: COC(=O)[C@H](CS)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)O)ccc1Cl
Reaction time: 3 h

Procedure:
To a solution of 5.1 g of tert-butyldimethylsilyl 2-bromomethyl-3-(tert-butyldimethylsilyloxy)-4-chlorobenzoate and 3.52 g of N-[N-(tert-butoxycarbonyl)-L-seryl]-L-cysteine methyl ester in 55 ml of methylene chloride was added within 30 minutes, at 0° C., a solution of 1.59 g of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in 15 ml of methylene chloride. Stirring was continued for 3 hours at 0° C., and subsequently the mixture was diluted with methylene chloride and stirred together with 100 ml of 1N aqueous acetic acid. The organic phase was washed with 10% sodium chloride solution, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was chromatographed on MCI-Gel CHP20P using as eluent a mixture of acetonitrile-water containing 40-0% water. The product was eluted with pure acetonitrile. Evaporation of the solvent afforded 2.7 g of 2-[[[(R)-2-[(S)-1-tert-butoxyformamido )-3-hydroxypropionylamino]-2-methoxycarbonyl-ethyl ]thio]methyl]-3 -(tert-butyldimethylsilyloxy)-4-chlorobenzoic acid as a white foam.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.[C:22]1([CH2:28][C@H:29]2[CH2:33][O:32][C:31](=[O:34])[NH:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC>ClCCl.C1COCC1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([N:30]2[C@@H:29]([CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33][O:32][C:31]2=[O:34])=[O:15])=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCc1ccc(CCCC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1ccc(CCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 60.8 %

Procedure:
4-(4-(1-n-Propyl)phenyl)butanoic acid (19.3 g) was disolved in dichloromethane and 25 mL of oxalyl chloride was added. After gas evolution ceased (~3 h) the mixture was concentrated in vacuo. To a solution of 4(S)-phenylmethyl-2-oxazolidinone (16.6 g, 93.6 mmol) in 250 mL of dry THF at -78° C. was added butyl lithium (64.4 mL, 1.6M, 102.99 mmol). After 5 min, a solution of the acid chloride in THF was added via cannula. After 15 min, the reaction was partitioned between ethyl acetate and 2N hydrchloric acid and the layers separated. The organics were washed twice with 2N hydrochloric acid and three times with dilute sodium bicarbonate then dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by flash filtration through silica-gel eluting with 10% ethyl acetate in hexane to give a pale-yellow oil which crystallized upon dissolution in 5% ethyl acetate in hexane. The mixture was concentrated and recrystallized from hexane to afford the title compound as colorless needles (20.8 g): 400 MHz 1H NMR (CDCl3) δ 7.4-7.0 (m, 9H), 4.63 (m, 1H), 4.14 (m, 2H), 3.20 (dd, 1H, J=3.30, 13.27 Hz), 2.97 (m, 2H), 2.73 (dd, 1H, J=9.72, 13.42 Hz), 2.67 (t, 2H, J=7.68 Hz), 2.53 (t, 2H, J=7.61 Hz), 2.00 (m, 2H), 1.61 (m, 2H), 0.92 (t, 3H, J=7.33 Hz).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(F)ccc2Sc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1Cc2cc(F)ccc2Sc2ccccc21

Procedure:
22 g of 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-one are suspended in 110 ml of ethanol and treated with 6.1 g of sodium borohydride. The mixture is heated under reflux for 10-15 minutes, then treated with water and extracted with chloroform. The organic phase is washed with water, dried over sodium sulphate and evaporated. There is obtained 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol which melts at 110°-113° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[OH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(CO)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2ccc(CO)cc2)nn1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-Hydroxymethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (4.35 g, 9.42 mmol) and lithiumhydroxide-hydrate (1.976 g, 47.1 mmol) in 80 mL MeOH and 80 mL water was stirred at 30° C. for 3 h. The methanol was evaporated in vacuo. The residual aqueous layer was washed with ethyl acetate, acidified with 1 N aq. HCl and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and evaporated to yield the crude product which was used in the next step without further purification. 1H-NMR (DMSO-d6, 400 MHz) 13.1 (broad s, 1H), 8.76 (s, 1H), 7.27-7.39 (m, 4H), 5.63 (s, 2H), 5.20 (t, 1H), 4.48 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.[F-:17].[Cs+]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[N:3]=[C:2]2[F:17]
Reactant: CC(C)Oc1cc2c(Cl)cccc2c(Cl)n1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)Oc1cc2c(Cl)cccc2c(F)n1
Temperature: 140 °C

Procedure:
To a solution of 1,5-dichloro-3-isopropoxyisoquinoline (598 mg, 2.335 mmol) in DMSO (5 mL) was added CsF (390 mg, 2.57 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with ethyl acteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. Crude material purified via silica gel chromatography (90 g column; 0-40% EtOAc:Hex) to get the product 5-chloro-1-fluoro-3-isopropoxyisoquinoline (520 mg, 93% yield) as a yellow solid. MS: MS m/z 240.15(M++1).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=NN[CH:14]=2)[CH:5]=1.C(O)(=O)C.C(OCC)(=O)C>CCOCC.C(O)C>[CH3:3][N:1]1[N:11]=[C:10]([C:6]2[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=2)[CH:14]=[N:2]1
Reactant: C=[N+]=[N-]
Reactant: c1cncc(-c2c[nH]nn2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1ncc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ca. 3.0 g (0.070 mol) diazomethane in ether was added dropwise to a solution of 6.0 g (0.04 mol) of 68 in 150 ml of ethanol at room temperature. The solution was stirred overnight at ambient temperature. Ca. 1 ml of acetic acid was added and the mixture was evaporated in vacuo. Water (75 ml) was added and the solution made basic with ammonia. Extraction with 3×100 ml of ether, drying of the organic phase over magnesium sulphate, and removal of the solvent in vacuo gave a brown solid which as applied to a silica gel column (eluent: ethyl acetate) giving a colorless solid, 69. Yield: 2.8 g (0.018 mol, 43%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[CH3:21][C:22]1([CH3:29])[CH2:27][C:26](=[O:28])[O:25][C:23]1=[O:24]>O1CCOCC1>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:26](=[O:28])[CH2:27][C:22]([C:23]([OH:25])=[O:24])([CH3:29])[CH3:21])[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Solvent: C1COCCO1
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CC(C)(C)C(=O)O

Procedure:
A solution of 3.6 g (13.5 mmol) of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 1.75 g (13.5 mmol) of 2,2-dimethylsuccinic acid anhydride in 50 ml of dioxane is heated under reflux for 5 hours. Concentration of the reaction mixture by evaporation yields crude 3-carboxy-3-methyl-butanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide that melts at from 125° to 131° and is further used in crude form.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)(=[S:3])[NH2:2].Cl[CH:17]([CH:20]=O)[CH:18]=[O:19].C(=O)([O-])[O-].[Mg+2]>O1CCOCC1>[CH:18]([C:17]1[S:3][C:1]([CH:4]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]2)=[N:2][CH:20]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)C1
Reactant: O=CC(Cl)C=O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(C=O)s2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-carbamothioylpyrrolidine-1-carboxylate (5 g, 21.71 mmol), 2-chloromalonaldehyde (3.70 g, 34.7 mmol) and magnesium carbonate (1.830 g, 21.71 mmol) were combined in dioxane (100 ml). The mixture was heated to 60° C. for 3 hours, stirred overnight at room temperature and then filtered through a pad of diatomaceous earth, rinsing with dichloromethane. The filtrate was concentrated in vacuo and then purified by normal phase chromatography to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.BrN1C(=O)CCC1=O.Cl.[C:20]([O:24][C:25](=[O:29])[CH2:26][NH:27][CH3:28])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O.CC(N=NC(C#N)(C)C)(C#N)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:1][N:27]([CH3:28])[CH2:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:29])=[CH:3][C:4]=1[Cl:10])#[N:7]
Reactant: Cc1ccc(C#N)c(Cl)c1
Reactant: CNCC(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)c(Cl)c1
Temperature: 100 °C
Yield: 83.5 %

Procedure:
A solution of 4-methyl-2-chlorobenzonitrile (1.51 g, 10 mmol), N-bromosuccinimide (2.14 g, 12.0 mmol) and AIBN (33 mg, 0.20 mmol) in ACN (40 mL) was heated under reflux for 18 hours. The reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of Na2CO3 and brine. The organic layer was dried (MgSO4) and concentrated under vacuum. The residue was treated with sarcosine tert-butyl ester hydrochloride (1.44 g, 7.92 mmol) and K2CO3 (2.74 g, 19.8 mmol) in ACN (10 mL). The mixture was heated at 100° C. for 2 hours. The solvent was evaporated under vacuum. The residue was dissolved in a mixture of DCM and water and then poured through a hydrophobic frit. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (silica, iso-hexane/Et2O) to afford the title compound (1.95 g, quantitative). 1H NMR (CDCl3, 400 MHz) δ 7.61 (1H, d, J=8.0 Hz), 7.57 (1H, s), 7.36 (1H, m), 3.73 (2H, s), 3.21 (2H, s), 2.36 (3H, s), 1.48 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: COCC(=O)Cl
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: COCC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and methoxyacetyl chloride. m.p.: 155-157° C.
Reaction SMILES: [C:1]([O:5][C@H:6]([CH3:11])[C:7]([O:9]C)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:12][CH2:13]C([O-])=O.[Na+].C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.Cl>C(OCC)(=O)C.C1COCC1>[Cl:12][CH2:13][C:7](=[O:9])[C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:11]
Reactant: O=C([O-])CCl
Reactant: COC(=O)[C@@H](C)OC(C)(C)C
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](OC(C)(C)C)C(=O)CCl
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A mixture of 8.00 g (50 mmol) of methyl (R)-2-(tert-butyloxy)propionate, 8.74 g (75 mmol) of sodium chloroacetate, 7.53 g (75 mmol) of triethylamine, and 200 mL of THF was cooled in ice, and 93.8 g (150 mmol) of a 1.6 M solution of tert-butylmagnesium chloride was added dropwise thereto over a period of 2 hours. After the completion of the dropwise addition, the reaction was performed at room temperature for another 2 hours, the reaction solution was cooled in ice again. Then, 20 mL of concentrated hydrochloric acid was added thereto, and subsequently 100 mL of ethyl acetate was added. Stirring was performed at room temperature for 1 hour. Then, the resulting organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7.35 g of a crude product. The resulting product was purified by column on silica gel to obtain 6.66 g of the title compound (yield: 80%). 1H-NMR (400 MHz, CDCl3) δ: 1.21 (s, 9H), 1.35 (d, 3H, J=6.6 Hz), 4.20 (q, 1H, J=6.6 Hz), 5.50 (s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=CC=CC=3)C=C4Cl)=NC=2[CH:7]=1)=O)C.[CH:38]1([N:44]2[C:48]3[CH:49]=[CH:50][C:51]([C:53]([OH:55])=[O:54])=[CH:52][C:47]=3[N:46]=[C:45]2[C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[N:62]=[C:61]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:60]=[C:59]3[N:72]([CH3:74])C)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.NCCCCO>>[CH:38]1([N:44]2[C:48]3[CH:49]=[CH:50][C:51]([C:53]([OH:55])=[O:54])=[CH:52][C:47]=3[N:46]=[C:45]2[C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[N:62]=[C:61]([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:60]=[C:59]3[NH:72][CH2:74][CH2:7][CH2:6][CH2:4][OH:3])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Agent: NCCCCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(NCCCCO)c3c1)n2C1CCCCC1

Procedure:
In this reaction 102 mg (0.2 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used in the same reaction sequence as that used for Compound 481. The nucleophile used was 4-amino-butan-1-ol. Yield: 59 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:20])[C:16]([CH2:18][OH:19])=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:20])[C:16]([CH2:18][O:19][C:22]3[CH:54]=[CH:53][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:52])=[CH:24][CH:23]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ccc(OCc3ccccc3)nc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Yield: 84.7 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 3.15 g of 5-benzyloxy-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 94), 5.50 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.91 ml of tributylphosphine, 2.95 g of 1,1'-(azodicarbonyl)dipiperidine and 100 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent, to give 7.10 g of the title compound, melting at 88-92° C. (softening).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:20]([O:29][CH3:30])[N:19]=1>O1CCOCC1>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:17][C:18]1[N:23]=[C:22]([NH:24][C:25]([CH3:26])([CH3:27])[CH3:28])[N:21]=[C:20]([O:29][CH3:30])[N:19]=1)=[O:15])(=[O:12])=[O:11]
Reactant: COc1nc(N)nc(NC(C)(C)C)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(NC(C)(C)C)n1

Procedure:
A mixture of 5.0 g of 2-difluoromethoxyphenyl-sulfonylisocyanate and 4.0 g of 2-amino-4-tert-butylamino-6-methoxy-1,3,5-triazine is stirred in 60 ml of absolute dioxane for 3 hours at 70°-80° C. After filtration of the hot reaction mixture through active charcoal, 6.9 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-tert-butylamino-6-methoxy-1,3,5-triazin-2-yl)-urea, m.p. 213°-214° C., crystallise out on cooling of the solution.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[O:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:43][C:39]3[O:38][CH:42]=[CH:41][N:40]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ncco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ncco3)ccc21
Reaction time: 0.08 h

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE AB, 40.69 mg, 0.074 mmol), oxazole-2-amine (9.32 mg, 0.11 mmol, Ryan Scientific, Mt. Pleasant, S.C.) and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (155 μl, 0.155 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the flask was lowered into an ice bath for 1 h. Additional portions of oxazole-2-amine (ca. 5 mg) and LHMDS solution (0.05 mL) were added in sequence. After an additional 45 min, glacial acetic acid (1 drop) was added. The mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(oxazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (br. s., 1 H), 8.38 (d, J=2.1 Hz, 1 H), 8.05 (dd, J=1.8, 8.8 Hz, 1 H), 7.71 (d, J=8.6 Hz, 1 H), 7.59 (d, J=1.7 Hz, 1 H), 7.31 (d, J=2.1 Hz, 1 H), 7.26-7.17 (m, 2 H), 6.80 (d, J=8.5 Hz, 1 H), 4.36-4.27 (m, 2 H), 3.87-3.82 (m, 2 H). m/z (ESI) 451.4 (M+H)+.