Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH2:5][OH:6].[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[Na+].[CH3:17][C:18]([CH3:20])=O>CCOCC>[CH3:17][C:18]1([CH3:20])[O:6][CH2:5][C:4]2[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:7]=2[O:10]1
Reactant: CC(C)=O
Reactant: OCc1cc(Br)ccc1O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CC1(C)OCc2cc(Br)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 5.0 g (24.63 mmol) 3-bromo-6-hydroxybenzyl alcohol in 30 ml acetone cooled to 0° C., a solution of 1.15 g (8.62 mmol) AlCl3 in 20 ml Et2O is added dropwise. The resulting mixture is allowed to stand at room temperature for 1 hr, after which time it is cooled to 0° C. and 50 ml of a 10% NaOH aqueous solution previously cooled to 5° C. is added thereto. The separated Et2O phase is washed twice with 20 ml H2O, dried on anhydrous Na2SO4, evaporated to dryness and distilled under reduce pressure to yield 4.85 g (81%) 2,2-dimethyl-6-bromobenzo-1,3-dioxane as an oil.
Reaction SMILES: C([O:3][C:4](=[O:41])[C@H:5]([OH:40])[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C>[Br:26][C:22]1[CH:21]=[C:20]([NH:19][C:17](=[O:18])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]([NH:7][CH2:6][C@@H:5]([OH:40])[C:4]([OH:41])=[O:3])=[O:39])=[CH:14][CH:13]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC[C@@H](O)C(=O)O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
(R)-3-{4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester (100 mg) was dissolved in ethanol (10 mL), 1 N sodium hydroxide (480 μL) was added and the resulting mixture was stirred at room temperature for 1 hour. 1 N Hydrochloric acid (480 μL) was added and the mixture was concentrated in vacuo. The residue was suspended in water (50 mL) and filtered to afford 38 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:23])[C:12]2[N:13]([N:15]=[C:16]([C:18]([O:20]CC)=[O:19])[CH:17]=2)[CH:14]=1.[OH-].[Na+].O.Cl>COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:23])[C:12]2[N:13]([N:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=2)[CH:14]=1
Reactant: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
500 mg (1.42 mmol) of ethyl 6-(2,4-dichlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carboxylate (Example 11A) were suspended in 60 ml of 1,2-dimethoxyethane, 1M aqueous sodium hydroxide (5.7 ml, 5.7 mmol) was added and the mixture was stirred at RT for 3 h. The reaction mixture was poured into water and acidified to pH 2 using 2M aqueous hydrochloric acid. The precipitate was filtered off and washed with water. Drying gave 430 mg (93% of theory) of the product as a solid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:16]O>>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CO
Reactant: NCCCCCCCC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCCCN
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To 15 ml methanol under nitrogen, stirred, at −5° C. was added thionyl chloride (0.80 ml) dropwise. After 5 minutes, 8-aminooctanoic acid (1.592 g, 10 mmol) was added. The reaction was stirred at −5° C. for 1 h, room temperature for 45 minutes, and 40° C. for 2.25 h. After heating, the reaction mixture was concentrated. The residue was taken up in chloroform/water (40 ml/25 ml) and basified to pH 9–10 using 1N NaOH. Layers were shaken, separated and the aqueous layer washed with water (2×30 ml). The combined organics were dried over Na2SO4 and filtered. The filtrate was concentrated in vac and dried to give the product as an oily solid (1.568 g, 90%); 1H NMR (400 MHz, DMSO-d6) δ 1.17–1.33 (m, 8H), 1.43–1.52 (m, 2H), 2.26 (t, J=7.5 Hz, 2H), 2.44–2.49 (m, 2H), 3.55 (s, 3H); IR (film) 3475, 2930, 2850, 1730 cm−1; mass spectrum [EI], m/z 173 M+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: Oc1ccc(OCCBr)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NCCOc2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 18.5 %

Procedure:
4-methoxy-aniline (124 mg, 1.0 mmol) and compound 5a (200 mg, 0.92 mmol) were reacted in acetonitrile (10.0 mL) for 30 mins and diisopropylethylamine was added (0.28 mL, 2.0 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated, purified by column chromatography to isolate the compound 5 as a colorless oil (45 mg, 0.17 mmol, 19% yield). MS (ESI, positive) m/z calcd. for C15H18NO3 [M+H]+: 260.13, found: 259.94. 1H NMR (CDCl3, 400 MHz) δ 6.66-6.84 (m, 8H), 4.45 (bs, 1H), 4.12 (t, J=5.2 Hz, 2H), 3.89 (bs, 1H), 3.77 (s, 3H), 3.47 (t, J=5.2 Hz, 2H).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C@H:6]2[CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11](=[O:12])[N:5]12)(=O)[NH2:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:1]([C@@H:4]1[CH2:8][S:7][C@H:6]2[CH2:9][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:11](=[O:12])[N:5]12)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2SC[C@@H](C#N)N2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 538 mg of tert-butyl (3R,6R,7aS)-(3-carbamoyl-5-oxohexahydropyrrolo[2,1-b]thiazol-6-yl)-carbamate in 35 ml of tetrahydrofuran was cooled in an ice bath and, after addition of 0.75 ml of triethylamine and 0.37 ml of trifluoroacetic anhydride, stirred at room temperature overnight. The volatile constituents were stripped off in vacuo at 30° C., and the oily residue was purified by column chromatography (silica gel, mobile phase: ethyl acetate:n-heptane=1:1).
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([CH:32]([CH3:34])[CH3:33])=[C:29]([SH:31])[CH:30]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:29]1[CH:30]=[C:25]([CH3:24])[CH:26]=[CH:27][C:28]=1[CH:32]([CH3:34])[CH3:33]
Reactant: Cc1ccc(C(C)C)c(S)c1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 66°-67° C.). 1H NMR (DMSO-d6) δ 1.16 (m, 6 H), 1.87 (s, 3 H), 2.26 (m, 3 H), 2.57 (m, 1 H), 3.23 (m, 1 H), 3.43 (q, 2 H), 6.01 (bs, 1 H), 6.78 (d, 1 H), 7.03-7.27 (m, 6 H), 7.37-7.47 (m, 5 H).
Reaction SMILES: [CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C:19](=[O:22])[CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C@H:19]([OH:22])[CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in J. Am. Chem. Soc., 1954, 76, 4013, (3β,5α,25R)-spirostan-3-ol-12-one was reduced with lithium aluminum hydride in ether to give a mixture of C-12 alcohols from which the title compound was isolated.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.[CH:27]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)=O.C(N(CC)CC)C.C([BH3-])#N.[Na+]>O1CCOCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Reactant: O=Cc1ccc2ccccc2n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Nc1nccn2c(C3CCN(Cc4ccc5ccccc5n4)CC3)nc(-c3cc4ccccc4[nH]3)c12

Procedure:
A solution of 1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30 mg, 0.09 mmol), 2-formylquinoline (17 mg, 0.11 mmol) and triethylamine (0.019 mL, 0.14 mmol) in 1,4-dioxane (1 mL) was treated with sodium cyanoborohydride (5.7 mg, 0.090 mmol) and microwaved at 300 watts, 120° C. for 20 min. The mixture was concentrated in vacuo, the residue was dissolved in methanol loaded onto an SCX ion exchange cartridge, and then eluted with 1M NH4OH in methanol. The semi-pure material thus obtained was then subjected to semi-preparative HPLC to afford desired product. 1H NMR (400 MHz, MeOD) δ ppm 2.13-2.33 (m, 4 H), 2.90 (t, J=10.86, 9.60 Hz, 2 H), 3.47 (d, J=10.11 Hz, 2 H), 4.29 (s, 2 H), 6.74 (s, 1 H), 7.02-7.11 (m, 2 H), 7.19 (t, J=8.08, 7.07 Hz, 1 H), 7.47 (d, J=9.09 Hz, 1 H), 7.58-7.65 (m, 3 H), 7.69 (d, J=8.59 Hz, 1 H), 7.80 (t, J=8.34, 6.82 Hz, 1 H), 7.96 (d, J=7.33 Hz, 1 H), 8.08 (d, J=8.34 Hz, 1H) and 8.39 (d, J=8.59 Hz, 1 H). MS (ES+): m/z 474.23 [MH+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1>CO.[Pd].[C]>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=C1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCOCC1
Yield: 95.9 %

Procedure:
A mixture of Example 219A (1 g) and 10% Pd/carbon (100 mg) in methanol(30 mL) was stiffed under hydrogen for 3.5 h, then filtered through a pad of celite and concentrated to give 0.97 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)#[N:30]>>[C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:33][CH:32]=1)#[N:30]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCc2ccc(-c3nccnc3NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)cc1
Yield: 73 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-cyanophenol, the title compound was isolated as a yellow solid in 73% yield (93% purity by HPLC).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:3]1[NH:2][N:1]=[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)[NH:4]1
Reactant: O=C([O-])O
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnn[nH]3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(C3=NNN(C)N3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide (44 mg, 0.172 mmol) in acetone (5 mL), sodium bicarbonate (84 mg, 1 mmol) and dimethyl sulfate (30 uL, 0.22 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (26 mg) and the other regioisomer (12 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:9]1([C:2]2[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: Cc1ncccc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncccc1C1=CCCCC1
Yield: 84.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using 3-bromo-2-methylpyridine (0.41 g, 2.40 mmol), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine) palladium (0)(0.14 g, 0.12 mmol), cesium carbonate (1.72 g, 5.29 mmol), 1,4-dioxane (8.0 mL) and water (4.0 mL), to yield the title compound (353.2 mg, 85%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:19][CH:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[CH2:13][CH:12]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([N:10]1[C:5]2[C:6](=[N:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[C:8]([C:11]2[CH2:19][CH:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[CH2:13][CH:12]=2)=[CH:9]1)(=[O:22])[CH3:21]
Reactant: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2n1
Reactant: CC(=O)Cl
Product: CC(=O)n1cc(C2=CCN3CCCC3C2)c2nc(N)ccc21
Yield: 72.7 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1,2,3,4,5,8-hexahydroindolizin-7-yl)pyrrolo[3,2-b]pyridine and 0.35 μL (0.47 mMol) acetyl chloride, 0.084 gm (73%) of the title compound were recovered by the procedure of Example 19.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)[CH3:17].[BH4-].[Na+].[OH-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][CH:21]1[CH2:22][CH2:23][N:18]([CH2:16][CH3:17])[CH2:19][CH2:20]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CCN1CCCCC1=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(NC3CCN(CC)CC3)ccc2[nH]1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
A mixture of 0.204 g (1 mmol) 5-amino-1H-indole-2-carboxylic acid ethyl ester, 133 mg (1 mmol) 1-ethyl piperidone and 0.35 ml (1 mmol) titanium(IV) isopropoxide in 1 ml methanol was treated after 3 h at room temperature with 0.023 g (1 mmol) sodium borohydride and the mixture was allowed to react during 16 h at room temperature. The mixture was poured on 50 ml ice/water and treated with 50 ml ethyl acetate and 5 ml 1 N NaOH aq. After 20 min the mixture was filtered through decalite and the aqueous phase was extracted with 50 ml ethyl acetate. The combined organic phases were washed with 50 ml NaCl sat., dried over Na2SO4 and after filtration evaporated to dryness. The residue was purified over silica eluting with a gradient of dichloromethane (DCM)/2N NH3 in methanol and 0.240 g (76%) of the title compound were isolated as brown solid. MS (m/e): 316.1 (MH+, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[IH:11]>CCOC(C)=O>[Cl:8][C:7]1[C:2]([I:11])=[N:3][C:4]([S:9][CH3:10])=[N:5][CH:6]=1
Reactant: CSc1ncc(Cl)c(Cl)n1
Reactant: I
Solvent: CCOC(C)=O
Product: CSc1ncc(Cl)c(I)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
4,5-dichloro-2-(methylthio)pyrimidine (23 g, 0.118 mol) was added to aq. HI (250 mL). The resulting mixture was stirred at room temperature for 24 h. TLC (Petroleum ether:EtOAc=4:1) indicated that the reaction was complete. The solid formed was collected and was treated with H2O (250 mL). The mixture was then adjusted to pH=7˜8 with solid K2CO3 and was extracted with CH2Cl2 (100 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and dried on vacuum to give title compound (29 g, 86%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:14]1([C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:8][CH:7]=2)([OH:11])[CH3:10])[CH2:16][CH2:15]1
Reactant: Br[Mg]C1CC1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(C(F)(F)F)cc1)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (7.97 mmol) of 4′-(trifluoromethyl)acetophenone and 31.9 ml (15.95 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.27 g (69% of theory) of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[CH2:22][C:23]([NH:25][O:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22]1[C:23](=[O:24])[N:25]([O:26][CH3:27])[C:2]2[N:3]=[C:4]([S:10][CH3:11])[N:5]=[CH:6][C:7]=2[CH:8]=1
Reactant: CSc1ncc(C=O)c(Cl)n1
Reactant: CONC(=O)Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COn1c(=O)c(-c2cc([N+](=O)[O-])ccc2Cl)cc2cnc(SC)nc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
4-Chloro-2-(methylthio)pyrimidine-5-carbaldehyde (90 mmol) and 2-(2-chloro-5-nitrophenyl)-N-methoxyacetamide (98 mmol) were dissolved in DMF (1 L) to give a brown solution. The reaction mixture was cooled to 0° C. Potassium carbonate (197 mmol) was added. The mixture was stirred at 0° C. for 2 h and then allowed to warm to room temperature over night. Potassium carbonate was filtered off and the filtrate was concentrated to approximately 100 mL. The residue was diluted with water (1 L) and filtered. The filter cake was washed with 350 mL of EtOH to give a brown solid that was dried in vacuum. The by-product (Z)-6-(2-chloro-5-nitrophenyl)-2-(methylthio)-7H-pyrano[2,3-d]pyrimidin-7-one O-methyl oxime was separated by reflux of the mixture for 4 h in EtOH and hot filtration of the suspension through a sintered glass funnel. Evaporation of the filtrate and drying gave 6-(2-chloro-5-nitrophenyl)-8-methoxy-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a solid (52%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>CC#N.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[N:6]=1)=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)c1n[nH]c2cc(Cl)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nn(C2CCCCO2)c2cc(Cl)ccc12
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
To a slurry of 6-Chloro-1H-indazole-3-carboxylic acid methyl ester (8.3 g, 39.5 mmol) in MeCN (200 mL) was added 3,4-Dihydro-2H-pyran (5.4 mL, 59.3 mmol) and p-toluenesulfonic acid (237 mg, 1.25 mmol). After letting the reaction stir for 10 minutes, saturated NaHCO3 (1 mL) was added and the solvent was removed by rotary evaporation to a volume of 100 mL. The mixture was diluted with EtOAc and washed with water (50 mL) and then with saturated NaCl (50 mL). The organic layer was then dried over Na2SO4. After the solids were removed by filtration, the organic layer was concentrated to an oil by rotary evaporation. The product was precipitated from the oil using hexanes to yield the desired product (7.667 g, 66% yield).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1B(O)O)[CH:13]([CH3:15])[CH3:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[O:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: Cc1ccc(B(O)O)c(OCC(C)C)c1
Product: Cc1ccc(-c2cccn3nc(Cl)nc23)c(OCC(C)C)c1

Procedure:
2-Chloro-8-(2-isobutoxy-4-methylphenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-isobutoxy-4-methylphenylboronic acid in a manner analogous to Example 2c (0.48 g, 71%). MS=316 (MH)+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:24]=[CH:23][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][OH:22])[O:20][C:15]=3[C:14]=2[CH2:25][CH2:26][CH3:27])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:3]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:24]=[CH:23][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][OH:22])[O:20][C:15]=3[C:14]=2[CH2:25][CH2:26][CH3:27])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:1])[CH3:3]
Reactant: CCCc1c(OCCCOc2ccc(C(C)O)c(OCc3ccccc3)c2CCC)ccc2c1OC(CO)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCc3ccccc3)c2CCC)ccc2c1OC(CO)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
To a solution of 8.9 g (16.2 mmole) of the title compound of Example 38 in 150 ml of methylene choride was added 18 g (162 mmole) of manganese dioxide. The reaction mixture was stirred at room temperature for 12 hours and filtered. Removal of the solvent gave 6.9 g of the title compound, mp. 83°-85°. Structure assignment was supported by nmr and infrared spectra.