Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[Br:14][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1
Reactant: CC(C)(O)c1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(O)c1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 2-hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.1 g, 30.5 mmol) in dicholoromethane (300 mL) was added carbon tetrabromide (8.81 g, 33.6 mmol) and triphenylphosphine (11.14 g, 33.6 mmol). The reaction was stirred at ambient temperature overnight then poured into a saturated solution of sodium bicarbonate. The organic layer was separated, concentrated to dryness and purified by column chromatography, eluting with a gradient of hexane to 3:1 hexane:ethyl acetate. The title compound (5.21 g, 74%) was obtained as a colourless oil; LC-MS Retention time 2.08 min, (M+H)+ 230, 232
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccccc1C(F)(F)F
Product: CCCCC(=O)Nc1ccccc1C(F)(F)F
Yield: 42.1 %

Procedure:
Using the procedure of Step A of Example 6, 32.22 g of o-trifluoromethyl aniline and 26.52 g of valeryl chloride were reacted to form 20.63 g of N-(2-trifluoromethylphenyl)-pentanamide melting at 63° C which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:29]([O-])=O)=[CH:4][C:5]([O:26][CH2:27][CH3:28])=[C:6]([CH:25]=1)[C:7]([NH:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12]1)=[O:8].C(O)C>C(OCC)(=O)C>[NH2:29][C:3]1[C:2]([Cl:1])=[CH:25][C:6]([C:7]([NH:9][CH2:10][CH:11]2[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12]2)=[O:8])=[C:5]([O:26][CH2:27][CH3:28])[CH:4]=1
Reactant: CCOc1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 70 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
Stannous chloride dihydrate (5.4 g) is added to a stirred mixture of 5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-4-nitrobenzamide (2.2 g), ethanol (30 ml), and ethyl acetate (30 ml). The reaction mixture is stirred at 70° C. for 2 hours and concentrated. The residue is basified with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is recrystallized from ethanol to give the title compound (1.1 g), mp 151°-153° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>C1S(=O)(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([Br:9])=[CH:11][CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: O=S1(=O)CCCC1
Product: Clc1cc(Nc2ccc(Br)cc2)ncn1
Yield: 11.1 %

Procedure:
4,6-Dichloropyrimidine (3.0 g, 20 mmol) was mixed with 4-bromoaniline (3.3 g, 19 mmol) and heated to 125° C. for two hours in tetramethylene sulphone. After cooling the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and EtOAc. The organic portion was washed, dried over sodium sulphate, filtered and evaporated. The residue was purified by column chromatography (EtOAc (20%): isohexane) to yield a solid (0.6 g, 11%). M/z 284 (MH)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][CH2:12][CH2:13][CH2:14][C@:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([NH2:20])[CH2:16][C:17]([CH3:19])=[CH2:18])[CH3:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([N:11]2[CH2:12][CH2:13][CH2:14][C@:15]([CH2:16][C:17]([CH3:19])=[CH2:18])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:20][C:37]2=[O:39])[CH3:10])=[CH:7][CH:8]=1
Reactant: C=C(C)C[C@@](N)(CCCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 157.3 %

Procedure:
A solution of (S)—N1—((S)-1-(4-bromophenyl)ethyl)-6-methyl-4-phenylhept-6-ene-1,4-diamine HCl salt (0.88 g, 2.2 mmol) in CH2Cl2 (120 mL) was cooled to 0° C. and i-Pr2NEt (1.15 mL, 3 equiv) was added. A solution of triphosgene (215 mg, 0.33 equiv) in CH2Cl2 (15 mL) was added dropwise over 10 min The mixture was stirred for 3 h at 0° C. LC-MS found the reaction completed. The mixture was concentrated, redissolved in 6:1 Ether/EtOAc (70 mL), washed with 1% aq HCl (2×15 mL), satd aq NaHCO3 (10 mL) and brine (10 mL), and dried over over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 40-g silica gel cartridge, eluted with a 5˜40% EtOAc in Hexanes gradient, to afford (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyl-1,3-diazepan-2-one (487 mg, 52%) as a clear oil. LC-MS Method 1 tR=2.25 min, m/z 427, 429 (M+1); 1H NMR (CDCl3) δ 7.42 (d, 2H), 7.35 (t, 2H), 7.28-7.20 (m, 3H), 6.76 (d, 2H), 5.37 (q, 1H), 5.21 (s, 1h), 4.98 (s, 1H), 4.85 (s, 1H), 2.78 (m, 2H), 2.44 (m, 3H), 1.89 (td, 1H), 1.43 (d, 3H), 1.24 (m, 1H), 1.11 (s, 3H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH:7]1[CH2:12][N:11]2[CH:13]=[CH:14][N:15]=[C:10]2[CH2:9][CH2:8]1.O>ClCCl>[N:15]1[CH:14]=[CH:13][N:11]2[CH2:12][CH:7]([OH:6])[CH2:8][CH2:9][C:10]=12
Reactant: COC1CCc2nccn2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: OC1CCc2nccn2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Add boron tribromide (1.24 mL; 2.0 equiv; 13.14 mmoles) to a solution of 6-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.0 g; 1.0 equiv; 6.57 mmoles) in dichloromethane (40 mL) dropwise and stir at ambient temperature for 4 hours. Add water (10 mL) and stir for 20 minutes, then concentrate the mixture. Add methanol (20 mL) and load the solution onto an scx ion-exchange column. Purify the product by eluting with methanol followed by 2M ammonia in methanol to give 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ol (0.908 g; 80% yield), which crystallizes upon standing. MS (m/z): 139 (M+1).
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]2[CH2:16][CH2:15]2)=[C:9]([N+:11]([O-])=O)[CH:10]=1>C(O)C.O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH:14]2[CH2:16][CH2:15]2)=[C:9]([CH:10]=1)[NH2:11]
Reactant: O=[N+]([O-])c1cc(Br)ccc1C1CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tin (II) chloride (16.0 g, 0.10 mol) is added in one portion to a solution of crude 5-bromo-2-cyclopropylnitrobenzene (8.68 g) in ethanol (190 ml) and water (1.9 ml). The reaction mixture is stirred at room temperature overnight, followed by addition of further tin (II) chloride (28 g, 0.175 mol) and additional stirring overnight. After concentration in vacuo ice is added, and the solution is basified with 2M aqueous sodium hydroxide. After extraction with ethyl acetate (×2) the organic phase is washed again with 2M aqueous sodium hydroxide, then also distilled water and brine. After drying over magnesium sulfate the solution is concentrated in vcauo to give a brown oil which is purified by flash column chromatography on silica gel (9:1 isohexane/ethyl acetate eluant) to afford 5-bromo-2-cyclopropylaniline as a brown oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:42][C:41]3[CH:43]=[CH:44][C:38]([CH2:37][N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)=[CH:39][CH:40]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(Cn2cncn2)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(Cn3cncn3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-1,2,4-triazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]([OH:15])=O.[N:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[CH:21]=[N:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[N:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[C:26]([NH:27][C:13]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[NH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[C:11]4[CH3:12])=[O:15])[CH:28]=[CH:29][CH:30]=2)[CH:21]=[N:20][CH:19]=1
Reactant: Nc1cccc(-c2cncnc2)c1
Reactant: Cc1c(C(F)(F)F)[nH]c2c(C(=O)O)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(C(F)(F)F)[nH]c2c(C(=O)Nc3cccc(-c4cncnc4)c3)cccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
To a suspension of 2-trifluoromethyl-3-methylindole-7-carboxylic acid (122 mg) and 3-(pyrimidin-5-yl)aniline (86 mg) in dichloromethane (3 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred at ambient temperature for 18 hours and diluted with dichloromethane. The solution was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[3-(pyrimidin-5-yl)-phenyl]-3-methyl-2-trifluoromethyl-1H-indole-7-carboxamide (106 mg, 53.5%).
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[NH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][CH:2]1[C:3](=[O:5])[C:18]2[C:17](=[CH:26][CH:25]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=2)[N:16]=[C:8]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(C)C(=O)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=O)C(C)C(c1ccccc1)=N2
Yield: 28.1 %

Procedure:
Ethyl alpha-methylbenzoylacetate (5 grams) and 3.67 grams of methyl p-aminobenzoate are dehydrated (by heating) for three days in 100 ml of chloroform in the presence of 0.7 gram of p-toluenesulfonic acid. p-Toluenesulfonic acid is removed therefrom, the filtrate is concentrated, and purified by silica gel column chromatography to give an oil. The resulting oily product is heated to reflux in 70 ml of diphenyl ether, cooled, and crystals which separate therefrom are collected by filtration and recrystallized from a mixture of dimethyl formamide and water to give 2 grams of methyl 3-methyl-2-phenyl-4-quinolone-6-carboxylate, colorless crystals, melting point above 300° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:16])=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:16])=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Nc1c(-c2cccnc2)cncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cncc(-c2cccnc2)c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 5-nitro-3,3′-bipyridin-4-amine (XLVII) (5 g, 23 mmol) in MeOH (20 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 15 h. The suspension was filtered through Celite and the concentrated under vacuum to produce 3,3′-bipyridine-4,5-diamine (XLVIII) as off white solid (3.3 g, 17.7 mmol, 76% yield). 1H NMR (DMSO-d6, 400 MHz,): δ 8.63-8.53 (m, 1H), 7.90-7.83 (m, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.48-7.43 (m, 2H), 6.13 (bs, 2H), 5.31 (bs, 2H). ESIMS found C10H10N4 m/z 187.10 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[C:16]1([N:13]2[CH:14]=[CH:15][C:10](=[N:9][C:29](=[S:30])[NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[N:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: S=C(N=c1ccn(-c2ccccc2)nc1)Nc1ccccc1
Yield: 40.6 %

Procedure:
5.3 g (52.4 millimoles) of triethylamine were added dropwise to 10.0 g (48.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 20 ml (22.6 g, 167 millimoles) of phenyl isothiocyanate at room temperature, while stirring. After the addition was complete, the reaction mixture was stirred for a further 2 hours at room temperature and then diluted with 30 ml of acetone. The product was filtered off under suction, washed with acetone, with water and again with acetone, and recrystallized from ethanol. 6.0 g (41% of theory) of 1,4-dihydro-1-phenyl-4-[(phenylthiocarbamyl)-imino]-pyridazine were isolated as orange crystals of melting point 171°-173° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].Cl.N1C=CC=CC=1.C(OCCO)C>>[OH:23][CH2:22][C:21]1[C:20]([CH3:27])=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1c(N)cccc1CO
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(CO)c3C)c2cc1OC
Temperature: 139 °C
Yield: 91.6 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.151 g (1.1 mmol) of 3-amino-2-methylbenzyl alcohol, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 6 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.32 g (91.5%) of the desired product as light tan crystals. MP 123-125° C.;: mass spectrum (electrospray, m/e,): 349.9(M+H)+.
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].N1C=CC=CC=1.P(Br)(Br)[Br:18].Cl>CCOCC>[Br:18][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: BrP(Br)Br
Reactant: O=C(O)CCCC#CCO
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(O)CCCC#CCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-5-heptynoic acid (88.2 g), described in Example 11, in anhydrous ether (300 ml) and pyridine (12 ml) is added dropwise phosphorus tribromide (67.5 g) at 10° C. The solution is stirred at room temperature for 30 min. then cooled to 5° C and 10% HCl (120 ml) is added slowly. The organic layer is washed with water and 10% sodium carbonate, dried (Na2SO4) and concentrated. The residue is distilled under reduced pressure to give 7-bromo-5-heptynoic acid, b.p. 146° C, 0.8 mm.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:23]=[CH:22][C:21]([CH:24]2[C:37]3[CH:36]=[CH:35][C:34]4[C:29](=[N:30][CH:31]=[CH:32][CH:33]=4)[C:28]=3[NH:27][S:26](=[O:39])(=[O:38])[N:25]2[CH3:40])=[CH:20][C:17]=1[CH:18]=O.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45]>ClCCCl>[F:15][C:16]1[CH:23]=[CH:22][C:21]([CH:24]2[C:37]3[CH:36]=[CH:35][C:34]4[C:29](=[N:30][CH:31]=[CH:32][CH:33]=4)[C:28]=3[NH:27][S:26](=[O:39])(=[O:38])[N:25]2[CH3:40])=[CH:20][C:17]=1[CH2:18][NH:45][CH2:44][CH2:43][N:42]([CH3:46])[CH3:41]
Reactant: CN1C(c2ccc(F)c(C=O)c2)c2ccc3cccnc3c2NS1(=O)=O
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)CCNCc1cc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.7 %

Procedure:
Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added to a solution of 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzaldehyde 422 (50 mg, 0.13 mmol) and N,N-dimethylethane-1,2-diamine (12.9 μl, 0.16 mmol) in DCE (2 ml) and the mixture was stirred at room temperature for 18 h. The reaction was quenched with sat. NaHCO3 solution (1 ml) and the mixture was extracted with EtOAc (5 ml). The organic phase was concentrated in vacuo. The crude residue was triturated from chloroform/MeOH to give the title compound (20 mg, 34%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].C(O)C.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccncc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (100 mg, 0.322 mmol), ethanol (4 mL), THF (0.8 mL), and sodium hydroxide (0.537 mL, 1.611 mmol). The final product was collected as 88 mg (97%). LCMS E-S (M+H)=283.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.4 Hz, 6 H), 5.40 (m, 1 H), 8.25 (d, J=5.6 Hz, 2 H), 8.32 (s, 1 H), 8.44 (s, 1 H), 8.79 (d, J=5.6 Hz, 2 H), 14.12 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]([C:19]3[C:20](=O)[NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=3)[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH:14]4[CH2:16][CH2:15]4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:28]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]([C:19]3[C:20](=[S:38])[NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=3)[C:10]3[N:11]=[C:12]([CH3:17])[N:13]([CH:14]4[CH2:16][CH2:15]4)[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:28]=1
Reactant: Cc1nc2c(n1C1CC1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1nc2c(n1C1CC1)C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A mixture of the product of step (i) (0.070 g) and Lawesson's reagent (0.350 g) in 1,4-dioxane (5 ml) was heated at reflux for 8 hours. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. Purification was by chromatography eluting with 0.2% 880 ammonia, 2% methanol in dichloromethane to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:22][C:23]([F:34])([F:33])[C:24]1[N:28]2[CH2:29][CH2:30][NH:31][CH2:32][C:27]2=[N:26][N:25]=1>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([N:31]4[CH2:30][CH2:29][N:28]5[C:24]([C:23]([F:34])([F:22])[F:33])=[N:25][N:26]=[C:27]5[CH2:32]4)=[O:19])=[CH:20][CH:21]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCn2c(nnc2C(F)(F)F)C1
Yield: 80.4 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.08 g, 0.27 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.053 g, 0.27 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone as a white solid (0.10 g, 78.1% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[NH:11][C:10]=2[CH2:21][CH3:22])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]([CH3:25])[C:10]=2[CH2:21][CH3:22])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCc1[nH]c2ccc(F)cc2c(=O)c1-c1cc(F)cc(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(-c2cc(F)cc(F)c2)c(=O)c2cc(F)ccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-(3,5-difluorophenyl)-2-ethyl-6-fluoroquinolin-4(1H)-one (280 mg, 0.9 mmol) in DMF (5 mL) was treated with NaH (60%, 1.5 eq, 55.3 mg). After 30 min, MeI (0.12 mL, 2.0 eq) was added dropwise and the reaction mixture was stirred at rt overnight before quenching with water. The reaction mixture was extracted with EtOAc (5 mL×2). The organic layers were combined washed with water, brine, dried, concd and purified by column chromatography on silica gel (EtOAc/hexane, 1/2) to give 3-(3,5-difluorophenyl)-2-ethyl-6-fluoro-1-methylquinolin-4(1H)-one as a white solid. Mass Spectrum (ESI) m/e=318 (M+1).
Reaction SMILES: C[Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:20]=[C:21](C(OCC)=O)[C:22]3[CH2:28][O:27][CH2:26][CH2:25][C:23]=3[N:24]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:20]=[C:21]([C:6]([OH:5])([CH3:7])[CH3:11])[C:22]3[CH2:28][O:27][CH2:26][CH2:25][C:23]=3[N:24]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: CCOC(=O)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc2c1COCC2
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(C(C)(C)O)n2)COCC3)ccc1-n1cnc(C)c1
Yield: 15 %

Procedure:
Methylmagnesium bromide (0.769 mL, 0.77 mmol) was added at 0° C. to a solution of ethyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-4-carboxylate (150 mg, 0.37 mmol) in dry THF (5 mL). 4 eq extra equivalents of methylmagnesium bromide were added over 2 h. The crude product was partitioned between DCM and water. The organic phase was separated and the solvent was evaporated. The crude product was purification on a prepHPLC affording 2-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)propan-2-ol (11.00 mg, 7.59%). MS (ES+) m/z 396.2 (M+H)+;
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].[CH3:20]S(C)=O>>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]2([C:2]([F:1])([F:18])[F:19])[CH2:20][O:17]2)[CH:13]=1
Reactant: CS(C)=O
Reactant: COc1ccc(Br)cc1C(C)(C)CC(=O)C(F)(F)F
Product: COc1ccc(Br)cc1C(C)(C)CC1(C(F)(F)F)CO1

Procedure:
To a solution of 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-4-methylpentan-2-one (5 g, 14.7 mmol) in 5 mL of anhydrous DMSO at room temperature was added 14.6 mL of the ylide stock solution (17.3 mmol) over 5 minutes. The reaction was quenched after 2 hours with water and diethyl ether. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-[2-(5-bromo-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane as a dark yellow oil.