Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9]S(C(C)(C)C)=O)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.[ClH:16].O1CCOCC1>CO>[Cl-:16].[CH:1]1([C@@H:4]([NH3+:9])[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1
Reactant: Cl
Reactant: CC(C)(C)S(=O)N[C@H](C1CC1)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Product: [Cl-]
Product: [NH3+][C@H](C1CC1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-2-methylpropane-2-sulfinamide ((S,R), 16.55 g, 68.0 mmol) was dissolved in MeOH (34 ml) and 4 M HCl in dioxane (34.0 ml, 136 mmol) was added. The reaction mixture was allowed to stir for 30 min, and concentrated to half the volume. Ether was added to the mixture, and the resultant precipitate was collected by filtration to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: ClCCCI
Reactant: Cc1ccc2c(c1)OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)OCC(=O)N2CCCCl
Yield: 78.6 %

Procedure:
7-Methyl-4H-benzo[1,4]oxazin-3-one (81MF2246a) (1.42 g, 8.7 mmol), Cs2CO3 (4.24 g, 13.0 mmol) and 3-chloro-1-iodopropane (1.95 g, 9.5 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2246b) (1.64 g, 79%). 1H NMR (CDCl3) δ 6.98-6.81 (m, 3H), 4.59 (s, 2H), 4.06-4.03 (m, 2H), 3.63-3.60 (m, 2H), 2.26 (s, 2H), 2.20-2.15 (m, 2H); 13C NMR (CDCl3) δ 164.8, 145.8, 134.3, 123.9, 118.1, 114.9, 68.0, 42.8, 39.4, 30.5, 21.0
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[C:2]1=[O:1])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Oc1ncccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cn1cccc(C(F)(F)F)c1=O
Yield: 84 %

Procedure:
As described in example 322a, reaction of 2-hydroxy-3-(trifluoromethyl)-pyridine with ethyl bromoacetate and potassium carbonate gave 2 products. The title compound was eluted second and was obtained as a colorless liquid (yield: 84%). MS: m/e=250.1[M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:25][CH:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:47][NH2:48].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:25][CH:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:48][OH:47])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)ON
Reactant: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[3-(methoxycarbonyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 43) (200 mg, 0.49 mmol) and N-methylmorpholine (59 μl, 0.54 mmol) in anhydrous dichloromethane (7 ml) was cooled to 0° C., treated with isobutyl chloroformate (70 μl, 0.54 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (175 μl, 1.47 mmol) was added and the mixture was for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with aqueous citric acid solution (10% w/v, 10 ml) and stirred for 2 hours. This mixture was then diluted with water and extracted with ethyl acetate (×3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLC to afford the title compound as a foam (150 mg).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[C:25]([CH3:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[NH:36]1[CH2:44][CH2:43][CH:39]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:37]1>O>[NH2:30][C:27]1[N:26]=[C:25]([CH3:31])[C:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([N:36]4[CH2:44][CH2:43][CH:39]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:37]4)[N:10]3[CH2:32][CH:33]3[CH2:35][CH2:34]3)=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)=[CH:29][N:28]=1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: NC(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(C(N)=O)CC3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and isonipecotamide (191 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 2.5 hours. The reaction mixture was left standing to cool followed by the addition of water and the insoluble matter was collected by filtration and dried to give 1-[2-(2-amino-4-methylpyrimidin-5-yl)-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-8-yl]piperidine-4-carboxamide (85 mg, 69%) as a pale yellow solid.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:19])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.Cl.C(=O)(O)[O-].[Na+].[C:26](OCC)(=O)[CH3:27]>C(O)C>[OH:1][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:19][CH2:26][CH3:27])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1
Reactant: ON=Cc1ccc(C(O)C#Cc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(C#Cc1ccccc1)c1ccc(CNO)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 5 g of 1-(4-hydroxyiminomethylphenyl)-3-phenyl-prop-2-yn-1-ol syn/anti-mixture prepared according to Example 1 and dissolved in 120 ml of ethanol were added 8 ml of borane-pyridine complex at 0° C. and then 12 ml of an ethanolic 20% by weight solution of hydrochloric acid. After stirring at 0° C. for one hour and at 20° C. for 2 hours, the reaction mixture was added to 1.2 liters of a saturated aqueous solution of sodium bicarbonate and shaken with ethyl acetate. The organic layer was dried over magnesium sulfate. After filtration and evaporation of the solvent at 40° C. and 2.7×103Pa, the resulting residue (8.1 g) was chromatographed with methylene chloride/methanol 4.7:0.3 to yield 2.3 g of 1-(4-hydroxyaminomethylphenyl)-3-phenyl-1-ethoxy-prop-2-yne in the form of a colorless oil. Following the procedure of Example 1, the resulting oil was converted into N-acetoxy-N-[4-[ 1-ethoxy-3-phenyl-prop-2-yn-1-yl]-benzyl]acetamide and then into the yellow oil of N-hydroxy-N-[4-[1-ethoxy-3-phenyl-prop-2-yn-1-yl]benzyl]acetamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1[SH:22])=[O:11].C(N(CC)CC)C.II>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:10](=[O:11])[C:12]2[CH:13]=[N:14][C:15]3[CH:16]=[C:17]4[O:25][CH2:24][O:23][C:18]4=[CH:19][C:20]=3[C:21]=2[S:22]1
Reactant: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1S)OCO3
Agent: II
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1c2cnc3cc4c(cc3c2sn1CCc1ccccn1)OCO4
Yield: 83 %

Procedure:
To 4.1 g (0.012 mol) of 8-mercapto-[1,3]dioxolo-[4,5-g]quinoline-7-carboxylic acid (2-pyridin-2-yl-ethyl)-amide (from Preparation 34) and 5 mL (0.035 mol) of triethylamine in 750 mL of methanol was added 2.95 g (0.012 mol) of iodine in 100 mL of methanol. The mixture was heated at reflux for 2 hours, cooled, and then concentrated to an oil. The residue was slurried in water, and the solid was collected and recrystallized in ethanol to give 3.5 g of the title compound, mp 200°-201° C.
Reaction SMILES: [NH2:1][C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:5][OH:6])[CH2:3][OH:4].[Na].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=1)[C:20]([NH:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH3:24])=[O:21]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:3][OH:4])[CH2:5][O:6][CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=1)[C:20]([NH:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[CH3:24])=[O:21]
Reactant: NC(CO)(CO)Cc1ccccc1
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cc(COCC(N)(CO)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of intermediate I 2-amino-2-benzylpropane-1,3-diol (0.09 g, 0.50 mmol) in 2 mL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.5 mL, 0.50 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (0.1 g, 0.23 mmol) in 1 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h, quenched with water, extracted with EtOAc, washed with aq LiCl (3×), dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (40 g silica, 0->8% (10% NH4OH in MeOH)/CH2Cl2) to afford 3-[(2-amino-2-benzyl-3-hydroxypropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 7.80 (s, 2H), 7.64 (s, 1H), 7.44-7.40 (m, 2H), 7.26-7.20 (m, 5H), 7.07-7.02 (m, 2H), 5.24 (q, J=7.0 Hz, 1H), 4.61 (s, 2H), 3.48 (A of AB, d, J=10.4 Hz, 1H), 3.43 (B of AB, d, J=10.4 Hz, 1H), 3.35 (s, 3H), 2.91 (s, 3H), 2.72 (A of AB, d, J=13.9 Hz, 1H), 2.66 (B of AB, d, J=13.9 Hz, 1H), 1.57 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([O:17]CC)=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cn(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
E1 (2 mmol, 1.0 eq.) and KOH (6 mmol, 3.0 eq.) in THF/H2O (1/1, 30 mL) were heated for 2 h at 60° C. The mixture was cooled to RT and then acidified with aq. HCl-solution (1N) to pH=1. The aq. phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4. Removal of the solvent yielded the product E2 as a yellow solid (450 mg, 95%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.80 (s, 3H), 7.37 (dd, J=J=9.0 Hz, 2H), 7.87 (dd, J=9.0 Hz, J=4.7 Hz, 2H), 8.40 (s, 1H), 12.72 (br s, 1H). MS (ES) C11H9FN2O3 requires: 236. Found: 237 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH:23][C:24](=[O:26])[CH3:25])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC(/C=C\C2N=C(NC(=O)C)SC=2C2C=CC=CC=2)=CC=1)([O-])=O.CO.C1COCC1>[C].[Pd].CC(O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:23][C:24](=[O:26])[CH3:25])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)c(-c2ccccc2)s1
Agent: [Pd]
Agent: CC(=O)Nc1nc(/C=C\c2ccc([N+](=O)[O-])cc2)c(-c2ccccc2)s1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of N-{4-[(E)-2-(4-nitrophenyl)vinyl]-5-phenyl-1,3-thiazol-2-yl}acetamide and N-{4-[(Z)-2-(4-nitrophenyl)vinyl]-5-phenyl-1,3-thiazol-2-yl}acetamide (E:Z=2:1) (600 mg), 10% palladium carbon (657 mg), MeOH (6 ml), THF (6 ml) and AcOH (1 ml) were combined. The reaction mixture was stirred under 3 atm H2 at r.t. for 3.5 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. 1N-NaOH was added to the residue, and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo to give N-{4-[2-(4-aminophenyl)ethyl]-5-phenyl-1,3-thiazol-2-yl}acetamide (528.6 mg) as a pale brown amorphous substance.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)[C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:40][N:39]=[N:38][N:33]=3)=[CH:24][CH:25]=2)[C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nn2cc(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1nn2cc(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 44 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step B and C) with trimethyltin azide according to the procedure of Example 1, Step G, gave a 44% yield of the title compound as a light tan solid, mp >160° C. (gradual); homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:11][CH:12]=[CH:13][Cl:14]>>[Cl:1][CH:2]([Cl:6])[C:3](=[O:4])/[C:13](/[Cl:14])=[CH:12]/[Cl:11]
Reactant: ClC=CCl
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(/C(Cl)=C/Cl)C(Cl)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
At room temperature, dichloroacetyl chloride (50 g, 0.339 mol) was added dropwise (slightly exothermic) to a suspension of AlCl3 (45 g, 0.339 mol) in 1,2-dichloroethylene (49.3 g, 0.508 mol). The reaction mixture was stirred under reflux conditions for 3 h and then at room temperature overnight. The reaction mixture was then stirred into ice water (500 g) (foams and reacts violently) and extracted three times with methylene chloride (200 ml). The combined organic phases were washed once at 10° C. with a saturated aqueous NaHCO3 solution and dried over magnesium sulfate, and the solvent was removed at a bath temperature of 70° C. at atmospheric pressure. The residue was subjected to incipient distillation at 50 mbar and 70° C. This gives 46.5 g of a black oil having a (Z)-1,1,3,4-tetrachlorobut-3-en-2-one content of about 70% and contains 25% of a byproduct, which is (Z)-1,1,1,4-tetrachlorobut-3-en-2-one. Accordingly, the yield of (Z)-1,1,3,4-tetrachlorobut-3-en-2-one is 38%.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1.[CH3:12][N:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=O)[O:15]C1=O.Cl>CCCCCC.O.O1CCCC1>[CH3:12][NH:13][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16](=[O:15])[CH2:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1
Reactant: Cc1nnn[nH]1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CNc1ccccc1C(=O)Cc1nnn[nH]1
Reaction time: 1 h

Procedure:
A solution of butyl lithium in hexane (1.6M, 67.5 ml) was added to a stirred mixture of 5-methyltetrazole (4.54 g), and dry tetrahydrofuran (200 ml) at 0°. After stirring for 1 hour, 1-methyl-1H-3,1-benzoxazine-2,4-dione (9.6 g) was added and stirring continued for 65 hours at room temperature. The mixture was poured into water (300 ml) and acidified with 5N hydrochloric acid (12 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×200 ml). The organic phases were combined, dried over anhydrous magnesium sulphate, and evaporated. The resulting solid was triturated with dichloromethane:industrial methylated spirit 9:1 (200 ml). The solid product was collected and recrystallised from ethyl acetate to give the novel compound 1-(2-methylaminophenyl)-2-(1H-tetrazol-5-yl)ethanone, m.p. 199°-201°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1.[CH:18](N1CCCCC1)=[O:19].Cl>O1CCCC1.O>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH:18]=[O:19])=[C:12]([F:17])[CH:11]=1
Reactant: O=CN1CCCCC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
55 ml (0.11 mmol) of 2 M lithium diisopropylamide are added with stirring at −70° C. to a solution of 19.3 g (0.1 mmol) of 1-bromo-3,5-difluorobenzene in 120 ml of dried tetrahydrofuran. After 30 minutes, N-formylpiperidine is added dropwise at this temperature. The mixture is allowed to warm to 0° C. At about 0° C., the reaction mixture is poured into cold water, acidified using 10% HCl and extracted twice with methyl tert-butyl ether. The combined organic phases are washed with water, dried over Na2SO4 and filtered, and the solvent is removed under reduced pressure. The residue is filtered through SiO2 (heptane/dichloromethane 1:1), (yield: 17.6 g, 78%).
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(-c2cncnc2)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 161.1, 72 mg, 0.15 mmol), pyrimidin-5-ylboronic acid (18.7 mg, 0.15 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (5.3 mg, 0.0075 mmol) and the mixture was subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=2.05 min, m/z=434.1 [M+H]+, m/z=432.1 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([SH:14])[CH:5]=1.C(N(CC)C(C)C)(C)C.Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([S:14][CH2:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:5]=1
Reactant: COC(=O)c1cc(S)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(SCCCC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-mercapto-5-trifluoromethyl-benzoic acid methyl ester (990 mg, 4.19 mmol) in acetonitrile (25 mL) were added N,N-diisopropylethylamine (1.08 g, 1.46 mL, 8.38 mmol) and tert-butyl 4-bromobutanoate (935 mg, 4.19 mmol, CAS RN 110611-91-1). The clear yellow solution was stirred at room temperature for 2.5 hours and then poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow liquid (1.27 g, 80%). MS (ESI+): m/z=379 ([M+]).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)#[CH:19]>CCCCCCC.CCOC(C)=O>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:18]#[C:19][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: FC(F)(F)c1ccc(C#Cc2cccnc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and 1-ethynyl-4-trifluoromethyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (87 mg, 70%); 1H NMR δ (CDCl3): 8.75-8.73 (m, 1H), 8.49-8.52 (m, 1H), 7.76-7.73 (m, 1H), 7.49-8.46 (m, 2H), 7.23-7.19 (m, 1H), 6.87-6.84 (m, 2H); LCMS m/z: 247.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=1)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[C:14]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[OH:13])[CH2:6][CH2:5][OH:4])(=[O:16])[CH3:15]
Reactant: CC(=O)OCCc1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(CCO)ccc1O
Yield: 108.1 %

Procedure:
A solution of 2-(3-acetyl-4-hydroxyphenyl)ethyl acetate (35.7 g) in ethanol (400 ml), and sodium bicarbonate (42 g) in water (200 mls) was refluxed for 81/2 hours. The ethanol was removed on a `Rotavapor` and the residue was extracted with ether (3x). The combined ethereal extracts were washed with water, sodium bicarbonate solution, saturated brine solution, dried over anhydrous magnesium sulphate, and evaporated to yield a red oil (31.3 g). The oil was recrystallised from hexane and ether (4:1) to yield the product as a pale yellow crystalline solid (18.3 g). The mother liquors were concentrated and an additional batch of product was obtained as a pale yellow crystalline solid (9.3 g).
Reaction SMILES: [C:1]1([C:11]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)(O)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O>[C:1]1([C:11]([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: C=C(c1c[nH]cn1)c1cccc2ccccc12

Procedure:
1-Naphthalen-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H1) in acetic acid:water (˜2:1) was heated to 100° C. for 1 h. The mixture was basified with 1 M NaOH and extracted (6×) with CHCl3:iPrOH (3:1). The organic solution was dried over MgSO4, filtered, and concentrated onto silica gel. The material was eluted from a column of silica with 5% NH3-MeOH:CH2Cl2 to give 4-(1-naphthalen-1-yl-vinyl)-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1ccc2ccccc2n1
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC1CCc2ccccc2N1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
In 60 ml of methylene chloride, 1.00 g of 2-methylquinoline was dissolved, and the catalyst-containing mixture was added. After cooling to −10° C., 8.4 ml of a mixed solvent of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the mixture was stirred at the same temperature overnight to give 2-methyl-1,2,3,4-tetrahydroquinoline. The S-enantiomer was in excess and the optical purity was 86.4% ee.