Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14]OC(OC)N(C)C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][CH:14]=[CH:12]2
Reactant: COc1ccc([N+](=O)[O-])c(C)c1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]ccc2c1C
Reaction time: 0.67 h

Procedure:
A solution of 1-methoxy-2,3-dimethyl-4-nitro-benzene (5.0 g), N,N-dimethylformamide dimethylacetal (7.4 mL) and triethylamine (0.10 mL) in 25 mL of N,N-dimethylformamide was heated to reflux for 3 days under nitrogen. The volatiles were removed in vacuo and the resulting residue was dissolved in 40 mL of a 1:1 mixture of methanol and tetrahydrofuran. Raney nickel (50% slurry in water, 1 mL) was added to the solution, then hydrazine hydrate (2.7 mL) was added dropwise and the mixture was stirred for 40 min under nitrogen. The reaction mixture was filtered through a bed of celite and the filtrate was reduced in vacuo. The product was purified by column chromatography (30% ethyl acetate in hexanes) to yield 1.5 g of pure 5-methoxy-4-methyl-indole.
Reaction SMILES: [OH-].[Na+].C([O:11][CH:12]([O:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:13])(=O)C1C=CC=CC=1>O.CO>[OH:11][CH:12]([O:14][CH2:15][C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:13]
Reactant: CC(OCc1[nH]c2ncccc2c1C=O)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(O)OCc1[nH]c2ncccc2c1C=O
Temperature: 60 °C

Procedure:
A solution of sodium hydroxide (1.33 g, 33 mmol) in water (35 ml) was added to a solution of 1-benzoyloxyethyloxymethyl-7-azaindole-3-carboxaldehyde (5.4 g, 16 mmol) in methanol (45 ml). The mixture was heated at 60° C. for 1 h, then the solvent was concentrated to half the original volume. Water was added, and the product was extracted with dichloromethane, dried over magnesium sulfate, filtered then evaporated to dryness. The product was used without further purification. Yield 2.7 g (74%)
Reaction SMILES: [C:1]1([N:7]2[CH2:22][CH2:21][N:11]3[C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=4[NH:14][C:15](=[S:16])[N:10]3[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:23][S:16][C:15]1[N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:22][CH2:21][N:11]2[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[N:14]=1
Reactant: S=C1Nc2ccccc2N2CCN(c3ccccc3)CCN12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSC1=Nc2ccccc2N2CCN(c3ccccc3)CCN12
Reaction time: 8 h

Procedure:
To a mixture of 2,3,4,5-tetrahydro-3-phenyl-1H-[1,2,5]triazepino[1,2-a][1,2,4]benzotriazine-7(8H)-thione (3.1 g from Example 12) and potassium t-butoxide (1.29 g) in N,N-dimethylformamide (50 ml, dried over 4A molecular sieves) was added methyl iodide (2 ml) and the reaction flask was sealed rapidly. An exothermic reaction ensued. The solution was left at room temperature overnight. The solution was evaporated and the residue was extracted with chloroform. The extract was applied to a column (71×3.2 cm) of dry column grade neutral alumina prepacked in chloroform. Elution with chloroform furnished a major component. Appropriate fractions were evaporated to a syrup. Trituration with heptane gave crude titled product; wt. 2.21 g, (65%), mp=125°-127°. Recrystallization (with decolorization) from dichloromethane-heptane furnished pure product; mp=128°-130°, m/e (E.I.) 324; maxKBr 1589, 765, 748, 693 cm-1 ; pmr (100 MHz, DMSO-D6) 2.42 (3H, singlet), 3.29 (2H, triplet, J=6 Hz), 3.67 (2H, triplet, J=6 Hz), 3.81 (2H, triplet, J=6 Hz), 3.89 (2H, triplet, J=6 Hz), 6.64-7.34 (9H, overlapping multiplets).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[CH:15][C:14]=12.C(N(CC)CC)C>CN1CCCC1=O>[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([CH:28]4[CH2:33][CH2:32][N:31]([C:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)=[CH:15][C:14]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Reactant: O=C(Cl)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCN(C(=O)N3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of piperidine-1-carbonyl chloride (0.033 g, 0.224 mmol) in N-methyl-2-pyrrolidinone (1 mL) was treated with N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)-benzamide (0.05 g, 0.150 mmol) and triethylamine (0.042 ml, 0.299 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was purified by reverse-phase HPLC to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (t, J=5.9 Hz, 1H), 8.84 (d, J=7.0 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.91-7.84 (m, 2H), 7.76 (s, 1H), 7.50-7.44 (m, 1H), 7.42-7.36 (m, 2H), 4.67 (d, J=5.8 Hz, 2H), 3.71-3.62 (m, 2H), 3.16-3.10 (m, 4H), 2.89-2.68 (m, 3H), 1.81-1.72 (m, 2H), 1.68-1.44 (m, 8H); MS (ESI(+)) m/e 446 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[CH:3]([CH:16]1[NH:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:1].[ClH:1].[CH:3]([CH:16]1[CH2:17][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:19][CH2:20][N:21]1[CH2:32][C:33](=[O:34])[NH2:35])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)CBr
Reactant: COc1ccccc1CN1CCNC(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1CN1CCN(CC(N)=O)C(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
A mixture of 3-benzhydryl-1-(2-methoxybenzyl)piperazine dihydrochloride (44.5 mg), bromoacetamide (20.7 mg) and potassium carbonate (41.5 mg) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (70:1). The fractions containing the objective compound were collected, evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give 2-benzhydryl-1-carbamoylmethyl-4-(2-methoxybenzyl) piperazine dihydrochloride (21.6 mg) as a colorless powder.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:12].Br[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCCCCCCN1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCN1CCCCCCCC1=O
Yield: 74.1 %

Procedure:
Following example 10, 16.32 g of 50% sodium hydride-mineral oil dispersion (8.16 g NaH, 0.34 M), 40 g (0.283 M) of azacyclononan-2-one and 43 g (0.311 M) of 1-bromobutane was refluxed for 22 hours. The reaction mixture was diluted with benzene-tolune and was extracted with water. The organic phase was separated, dried and concentrated to a yellow oil. Distillation afforded 41.4 g (74%) of product; b.p. 166°-170°/0.2 mm.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:38])([F:37])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]CC(O)=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:31][CH:30]=2)[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCc1ccc(C(F)(F)F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.086 g, 0.27 mmol) and 3-(4-(trifluoromethyl)phenyl)propanoic acid (60 mg, 0.27 mmol) taken in dry DCM (20 mL), DIPEA (72 mg, 1.37 mmol) followed by HATU (208 mg, 0.55 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.118 g, 90.07%) as solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH2:21][CH3:22])[C:13](=O)[CH2:14][C:15]([O:17]CC)=[O:16]>>[CH2:21]([C:12]1[O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:13]=1[CH2:14][C:15]([OH:17])=[O:16])[CH3:22]
Reactant: CCOC(=O)CC(=O)C(Br)CC
Reactant: NC(=O)c1ccc(F)cc1
Product: CCc1oc(-c2ccc(F)cc2)nc1CC(=O)O

Procedure:
The title compound was prepared from 5 g of 4-fluorobenzamide and 5.67 g of ethyl 4-bromo-3-oxo-hexanoate as described in example 2B to give 1.8 grams of intermediate 3B as a solid: 1H NMR (CDCl3, 300 MHz) δ7.96 (dd, 2H, J=8.8, 5.3), 7.11 (t, 2H, J=8.6), 3.61 (s, 2H), 2.69 (q, 2H, J=7.5), 1.27 (t, 3H, J=7.5).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[N+:7]=1[O-:14].OS(O)(=O)=O.[OH-].[Na+]>>[Br:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=[C:8]([CH2:12][CH3:13])[N+:7]=1[O-:14]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(Br)[n+]1[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
With ice bath cooling HNO3 (100%, 25 ml) was added dropwise to 2-bromo-6-ethyl-pyridine 1-oxide (20.0 g, 99 mmol), followed by H2SO4 (98%, 17 ml). The mixture was stirred at 90° C. for 90 min and then cooled to rt. Crushed ice (500 g) was added and the mixture was made basic (pH 12) using 28% NaOH solution. After extraction with AcOEt (4×250 ml) the combined organic phases were dried (Na2CO3) and evaporated to give 15.9 g (65%) of a yellow Solid mass which was directly used in the next step
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[N+:29]([O-:52])[CH:30]=[C:31]([Cl:51])[C:32]=1[CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)O.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([O:25][C@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]3[CH2:49][CH2:50]3)[CH:37]=1)[CH2:33][C:32]1[C:31]([Cl:51])=[CH:30][N+:29]([O-:52])=[CH:28][C:27]=1[Cl:26])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O)c1)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)S(C)(=O)=O
Yield: 68 %

Procedure:
To a solution of 2-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (120 mg, 0.326 mmol) in DCM (10 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (137 mg, 0.326 mmol), EDC (187 mg, 0.977 mmol) and DMAP (19.90 mg, 0.163 mmol) were added, and the mixture was reacted at room temperature for 6 hours. The mixture was portioned between DCM and 1N HCl (50 ml) and the desired compound was extracted with DCM (3×50 ml). Crude (S)-4-(2-(2-(5-(N-(tert-butoxycarbonyl)-methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained and used in the next step without any additional purification (170 mg, 0.221 mmol, 68% yield). MS/ESI+ 770.1 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2ccc(F)c(Br)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Br)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 84A in analogy to the synthesis of the compound of Example 1. 26 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O1CCOCC1.[CH2:18]([N:24]=[C:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:25](=[O:26])[NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CCCCCCN=C=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 32 °C
Reaction time: 48 h

Procedure:
Mixture of quinolin-6-ol (0.58 g., 4 mmol), dry dioxane (20 ml), hexyl isocyanate (0.698 ml, 4.8 mmol) and dry pyridine (0.2 ml) was stirred at room temperature (32° C.) for 48 hours. Reaction mixture was concentrated under vaccum, titurated with water (1 ml) and crystallised with ether, to give 1a; yield: 0.80 g. (73.5%), m.p. 89° C., C16H20N2O2; 1H NMR δ ppm (CDCl3): 0.91 (bs, 3H), 1.33-1.34 (bs, 6H), 1.56-1.62 (m, 2H), 3.24-3.34 (m, 2H), 5.21 (bs, 1H), 7.35-7.42 (m, 1H), 7.48-7.52 (m, 1H), 7.60-7.61 (m, 1H), 8.07-8.12 (m, 2H), 8.86-8.89 (m, 1H); IR vmax (KBr) (cm−1): 478, 530, 674, 730, 788, 839, 909, 970, 1002, 1040, 1158, 1215, 1258, 1300, 1356, 1462, 1495, 1543, 1709, 1919, 2373, 2861, 2961, 3032, 3286, 3346, 3777, MS: m/z: 273 (M+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH:20]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][CH2:24][O:23][CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CC(C)OCCCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)OCCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 3-isopropoxypropylamine (0.197 g, 1.68 mmol) and 3 Å molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 30% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes). Concentrate the fractions containing the product. Take the solid tip in dichloromethane (100 mL) and wash with 1.0 N NaOH (2× 25 mL) to give the title compound (0.395 g, 71%): TOF MS ES+ 363.2 (M+H)+, HRMS calcd for C18H24N4O3F 363.1832 (M+H)+, found 363.1821, time 0.57 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=9.8 ml, 100% purity.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([C:13](=[O:15])[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[S:3][C:4]=4[CH:10]=3)=[O:16])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)sc2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-oxalamic acid (Example 61b) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 223.5-225.5° C. (diethylether)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: c1nc[nH]n1
Product: c1ccc(-n2cncn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-[1,2,4]triazole (104 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 120 mg (83% isolated yield) of the desired product as a light yellow solid.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([NH:11][CH2:12][C@H:13]([NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)(=[O:18])=[O:17])[CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C=O.[C:31]([BH3-])#N.[Na+]>C(O)C>[ClH:1].[ClH:1].[CH3:31][N:11]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][C@H:13]([NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)(=[O:18])=[O:17])[CH3:14]
Reactant: C[C@H](CNCCc1ccccc1)NS(=O)(=O)c1ccc2cnccc2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CN(C)CCc1ccccc1)NS(=O)(=O)c1ccc2cnccc2c1
Yield: 75.4 %

Procedure:
The compound of Example 23 (54 mg) was N-methylated by the action of paraformaldehyde (50 mg) and sodium cyanoborohydride (63 mg) in ethanol to obtain a crude product. Subsequently, 21 mg of the title compound was obtained as a gray solid (35%) with reference to the method of Step 3 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][CH:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[CH:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:38]([O:40][CH2:41][C:42]#[CH:43])=[O:39]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:32])[CH3:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:38]([O:40][CH2:41][C:42]#[CH:43])=[O:39])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CCOC(=O)Cl
Reactant: CC1=C[C@@H]2[C@H](C(C)C)CCC(C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)C1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCOC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To (1S,4aS,5S,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 144, 500 mg, 0.96 mmol) and 4-dimethylaminopyridine (350 mg, 2.9 mmol) in dichloromethane (25 ml) at 0° C. under nitrogen was added propargyl chloroformate (170 mg, 1.44 mmol) and the resulting mixture stirred at 0° C. for 30 minutes and at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with citric acid solution (3×50 ml) and water (2×50 ml), dried (MgSO4) and concentrated in vacuo to give a solid. The crude product was purified by flash chromatography on silica (40 g) eluting with hexane:ethyl acetate (3:2). The pure fractions were combined and concentrated in vacuo to give the title product (462 mg, 80%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[C:10]([C:17]([F:20])([F:19])[F:18])[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=O.C[O-].[Na+].Cl>CO.O>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23](/[CH:21]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][C:10]([C:17]([F:20])([F:18])[F:19])=[CH:11][CH:12]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2ccc(C(F)(F)F)nc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
A mixture of 1-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-ethanone (4.28 g, 15.3 mmol) in methanol (60.4 mL) at 25° C. was treated with methyl 4-formylbenzoate (3.01 g, 18.3 mmol) and sodium methoxide in methanol (25% wt, 6.99 mL, 30.5 mmol). The reaction was stirred at 25° C. for 2 d. At this time, the reaction was diluted with water (50 mL), neutralized with a 2N aqueous hydrochloric acid solution, and extracted with methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate and filtered. Silica gel was added to the filtrate, concentrated in vacuo and dried under high vacuum. Flash chromatography (40 g silica column, 10-100% ethyl acetate/hexanes) afforded 4-[(E)-3-oxo-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (4.04 g, 62%) as an orange solid.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[C:6]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:5]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Si:20]([O:19][C:6]1[CH:5]=[C:4]([OH:3])[CH:9]=[C:8]([Cl:10])[C:7]=1[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(OC=O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 1.236 g (2.97 mmol) of 3,4-bis-(t-butyldimethylsilyloxy)-5-chlorophenyl formate in 10 mL of methanol was added 2.05 g (15.0 mmol) of potassium carbonate at 25° C. The solution was stirred for 30 min., diluted with 35 mL of water, and extracted three times with diethyl ether (50 mL each). The combined extracts were washed with brine, dried (MgSO4), and concentrated to give 1.028 g (90% yield) of 3,4-bis-(t-butyldimethylsilyloxy)-5-chlorophenol. 1H NMR (CDCl3) d 6.45 (d, J=2.8 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 1.00 (s, 9H, t-Bu), 0.93 (s, 9H, t-Bu), 0.18 (s, 6H, Me), 0.15 (s, 6H, Me); 13C NMR (CDCl3) d 149.7 (s), 148.9 (s), 137.7 (s), 126.9 (s), 109.8 (d), 107.8 (d), 26.3 (q, 3C), 26.2 (q, 3C), −3.6 (q, 2C, Me), −3.4 (q, 2C, Me). Anal. Calcd for C18H33ClO3Si2: C, 55.57; H, 8.55. Found: C, 55.39; H, 8.87.