Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.CN.[C:24]([BH3-])#[N:25].[Na+].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:25][CH3:24])[CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
To a solution of 1-(4-biphenylyl)-2-(4-morpholinyl)ethanone (9.70 g, 34.4 mmol) in THF (100 ML) was added methylamine (2M solution in THF, 100 mL, 200 mmol). The mixture was stirred at room temperature for 15 min and then sodium cyanoborohydride (8.34 g, 133 mmol) and acetic acid (2.0 mL) were added. The resultant mixture was stirred at room temperature for 48 h. The mixture was diluted with ethyl acetate (200 mL) and washed with 5% NaHCO3 (200 mL) and water (200 mL). The organic layer was dried (MgSO4) and concentrated to give 10.59 g (100%) of the title compound as a yellow oil which solidified upon standing at room temperature. MS (ES) m/e 297.6 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=CC3[NH:48][C:49](=[O:52])[O:50]C=3C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[NH:48][C:49](=[O:50])[O:52][C:22]=5[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1[nH]c2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2o1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)oc54)c3=O)cc2)CCC1
Yield: 48 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-8-phenyl-3H-chromeno[7,8-d]oxazole-2,6-dione was reacted to give the title compound as a yellow oil (66 mg, 48%). LCMS (Method G): RT=3.95, [M+H]+=525.
Reaction SMILES: [C:1]1([C:7]2[O:13][C@H:12]3[C@H:9]([C:10](=[O:34])[N:11]3[C:14]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:15]([CH3:17])[CH3:16])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+].[CH2:48]([O:50][C:51](=[O:55])[C@H:52]([CH3:54])[OH:53])[CH3:49]>>[CH2:48]([O:50][C:51]([C@H:52]([O:53][C@H:12]1[N:11]([C:14]([C:18]([O:20][CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])=[C:15]([CH3:16])[CH3:17])[C:10](=[O:34])[C@@H:9]1[NH:8][C:7](=[O:13])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:54])=[O:55])[CH3:49]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: CCOC(=O)[C@@H](C)O[C@@H]1[C@@H](NC(=O)c2ccccc2)C(=O)N1C(C(=O)OC(c1ccccc1)c1ccccc1)=C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10 Grams of (1R,5S)-3-phenyl-6-(1-diphenylmethoxycarbonyl-2-methylprop-1-enyl)-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-ene as used in Example 9(1) was dissolved in 35 ml of L-(+)-lactic acid ethyl ester instead of the DL-α-lactic acid ethyl ester employed in Reference Example 1(1). To the resultant solution was added 0.5 ml of trifluoromethanesulfonic acid, and the mixture was stirred at ambient temperature for 1.5 hours. The reaction solution thus obtained was poured into 200 ml of aqueous sodium bicarbonate and allowed to stand under ice-cooling for 30 minutes.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][CH2:26][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)[CH:30]([CH3:32])[CH3:31])C.[CH2:36](I)[CH2:37][CH3:38]>CN(C)C=O>[Cl:22][C:21]1[C:16]2[C:15](=[O:23])[N:14]3[CH2:24][CH2:25][CH2:26][C@H:13]3[C:12]3[N:11]([CH:10]=[N:9][C:8]=3[C:6]3[O:5][N:4]=[C:3]([CH2:2][N:1]([CH2:36][CH2:37][CH3:38])[CH2:31][CH2:30][CH3:32])[N:7]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCI
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Yield: 35.6 %

Procedure:
1.85 g (5 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, 20 ml of N,N-dimethylformamide, 2.14 ml (12.5 mmol) of N-ethyldiisopropylamine and 0.97 ml (10 mmol) of propyl iodide were stirred at 80° overnight. After evaporating the solvent the residue was chromatographed on 210 g of silica gel while eluting with ethyl acetate. There was obtained 0.81 g (36%) of (S)-8-chloro-11,12,13,13a-tetrahydro-1-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 155°-158°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1F.Cl.[CH3:16][S:17]([CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].CS(C)=O>CCOC(C)=O.C(Cl)Cl>[CH2:12]([O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([CH3:1])=[C:3]([N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:23][CH2:24]2)[CH:4]=1)[CH3:13]
Reactant: CCOc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 66.2 %

Procedure:
To 1-(ethyloxy)-5-fluoro-4-methyl-2-nitrobenzene (Example 215, step A) (13.1 g, 65.9 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine hydrochloride (15.0 g, 65.9 mmol) and K2CO3 (31.9 g, 231 mmol) was added DMSO (300 mL). The reaction mixture was heated at 100° C. overnight. The reaction was cooled to rt and diluted with EtOAc and DCM. The organic layer was washed with H2O and the aqueous layer was backextracted with DCM. The combined organic layers were dried (MgSO4), filtered and rotovapped down. Purification by flash chromatography provided the title compound of Step F (16.2 g, 43.6 mmol, 66% yield). This reaction was carried out in duplicate to provide an overall amount of 33.2 g, 89.4 mmol of the title compound of Step F. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.56-6.73 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.30 (d, J=12.2 Hz, 2H), 3.04-3.15 (m, 2H), 2.95 (s, 3H), 2.74 (t, J=11.5 Hz, 2H), 2.26 (s, 3H), 1.81-1.97 (m, 4H), 1.42-1.74 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:13][CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In DMF (120 ml) was dissolved 4-bromobenzyl alcohol (10.1 g). To the mixture was added under ice-cooling 65% sodium hydride (3.6 g), and the mixture was stirred at room temperature for 3 hours. To the mixture was added dropwise at room temperature iodoethane (12.6 g),and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-4-(ethoxymethyl)benzene (10.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:24])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[C:44]([F:47])([F:46])[F:45])[C:38](Cl)=[O:39]>CC(N(C)C)=O.CS(C)=O>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:24][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:43]([C:44]([F:45])([F:46])[F:47])=[C:35]([F:34])[CH:36]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCOCC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(C(F)(F)F)c(F)c2)ccc1OCCN1CCCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine (0.06 g, 0.152 mmol), and N,N-diisopropylethylamine (0.0529 mL, 0.304 mmol) in 3.0 mL of DMA was added slowly 3-fluoro-4-(trifluoromethyl)benzoyl chloride (0.0278 mL, 0.182 mmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and subjected to purification on a RP-HPLC. The proper fractions were collected and lyophilized to furnish N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide as an off-white semisolid in 53% yield. LCMS m/z (%)=585 (M+H 79Br, 100), 587 (M+H 81Br, 98). 1H NMR (400 MHz, DMSO-d6) δ: 10.3 (bs, 1H), 8.06 (d, J=11.27 Hz, 1H), 7.95-8.01 (m, 3H), 7.72 (d, J=2.60 Hz, 1H), 7.68 (d, J=2.36 Hz, 1H), 7.31 (d. J=9.48 Hz, 1H), 4.35-4.44 (m, 2H), 3.5-3.9 (m, 10H), 2.51-2.69 (m, 5H).
Reaction SMILES: CS(N)(=O)=O.[CH:6]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1.[Cl:13][C:14]1[C:15]([O:24][CH:25]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]2)=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>CO>[Cl:13][C:14]1[C:15]([O:24][CH:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([NH:12][S:9]([CH:6]1[CH2:8][CH2:7]1)(=[O:11])=[O:10])=[O:20]
Reactant: O=C(O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Solvent: CO
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with cyclopropanesulfonamide and to replace 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid and methanol with cyclopropyl sulfonamide, the title compound was obtained as a colorless solid (0.047 g, 31%): 1H NMR (300 MHz, DMSO-d6) δ 12.02 (br s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.37 (d, J=12.6 Hz, 1H), 4.85 (br s, 1H), 3.07-2.98 (m, 1H), 2.07-1.87 (m, 8H), 1.09-1.05 (m, 4H); 19F NMR (282 MHz, DMSO-d6) δ −92.3 (d, J=231 Hz, 1F), −98.5 (d, J=231 Hz, 1F), −109.9 (s, 1F); MS (ES−) m/z 410.0, 412.0 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>O>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:2]3[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=3)=[CH:18][C:17]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1cccc(Br)c1
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)c3)cc21

Procedure:
Prepared according to the procedure B from 3-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 188-190° C. 1H-NMR (DMSO-d6) δ10.33 (s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1H, J=8.00 Hz), 7.33 (d, 1H, J=7.57 Hz), 6.99 (d, 1H, J=8.81 Hz) 4.09 (s, 2H), 1.67 (s, 6H); MS m/z 291(M−H). Anal. Calc. For (C18H16N2O2)2.0.3 H2O: C, 72.61; H, 5.62; N, 9.41. Found: C, 73.00; H, 5.43; N, 8.81
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:15]1([N:21]([CH3:32])[S:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C(=O)C.O>[F:1][C:2]([F:10])([F:9])[C:3]([OH:7])([CH3:8])[C:4]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([S:22]([N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:32])(=[O:24])=[O:23])=[CH:26][CH:27]=1)=[O:5]
Reactant: CN(c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1ccccc1)S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a cooled (-20° C.) solution of α-trifluoromethyl lactic acid 0.20 g in dry N,N-dimethylacetamide (4 ml) was added thionyl chloride (0.16 g). The reaction mixture was stirred for 1 hour, then warmed to 0° C. over 30 minutes and treated with 4-(N-phenyl-N-methylaminosulfonyl)aniline (0.34 g). After stirring at 22° C. for 24 hours, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2×20 ml). The combined ethyl acetate extracts were washed with brine, dried (Na2SO4) and concentrated at reduced pressure to give an oil which was purified by chromatography (1:1 hexane: ethyl aceate) and recrystallised from methyl-t-butyl ether/hexane to produce the title compound as a colourless solid (0.31 g); mp 147°-149° C.; MS: m/z=403(M+1); NMR (250 MHz): 1.55 (s,3), 3.09 (s,3), 7.05-7.08 (m, 2), 7.28-7.43 (m,5), 7.53 (s,1), 7.91-7.95 (m,2), 10.36 (broad s, 1). Analysis for C17H17F3N2O4S: Calculated: C, 50.78; H, 4.26; N, 6.97; Found: C, 50.80; H, 4.37; N, 6.93.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:12][C:6]2=[N:7][CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]2[CH:4]=1.[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:15][C:16]1[C:21]([C:22]([NH:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[NH:12][C:6]3=[N:7][CH:8]=2)=[O:23])=[C:20]([F:25])[C:19]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:18][CH:17]=1
Reactant: Nc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]c(C(F)(F)F)cc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.5 %

Procedure:
2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.040 g, 0.199 mmol), 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.064 g, 0.219 mmol), EDCI (0.042 g, 0.219 mmol) and HOBt (0.027 g, 0.199 mmol) were dissolved in DMF (0.6 mL) and stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase HPLC to give 6-chloro-2-fluoro-3-(propylsulfonamido)-N-(2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.050 g, 52%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.91 (s, 1H), 10.99 (s, 1H), 9.96 (s, 1H), 8.60-8.56 (m, 1H), 8.56-8.52 (m, 1H), 7.54 (t, 1H), 7.44 (d, 1H), 7.10 (s, 1H), 3.21-3.12 (m, 2H), 1.76 (m, 2H), 0.99 (t, 3H); m/z (ES-MS) 479.1 (100.0%) [M+1].
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>>[CH2:28]([N:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CBr
Reactant: COC(=O)CCc1ccc(OCc2cccc(Nc3ccccc3)c2)cc1
Product: CC(C)CN(c1ccccc1)c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 302 from methyl 3-[4-[(3-anilinobenzyl)oxy]phenyl]propanoate and isobutyl bromide. beige powder (yield 12%). MS (APCI−): 402 (M−H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=O)[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].O.[N+:27]([CH3:30])([O-:29])=[O:28]>>[N+:27](/[CH:30]=[CH:19]/[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([O-:29])=[O:28]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=[N+]([O-])/C=C/c1cccc2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
1-(Phenylsulfonyl)-1H-indole-4-carbaldehyde, Intermediate 5 (45.4 g, 0.159 mol) was dissolved in nitromethane (300 ml) and ammonium acetate (4.9 g, 0.064 mol, 0.4 eq.) was added. Mixture was heated at reflux for 4 hours and left overnight at ROOM TEMPERATURE Water (150 ml) was added, organic phase was separated. The aqueous phase was extracted with DCM (3×50 ml). Combined organic phase was washed with brine and dried on Na2SO4. The crude material (HPLC purity 85%) was passed through a silica column using DCM/EtOAc (8:1) as eluent. The product containing fractions were evaporated to a small volume when crystallization started. The yellow crystals were filtered, washed with petro/ether/EtOAc (2:1), and dried in vacuo. Yield: 33.1 g. MS m/z 329 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C(=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
Sodium hydride (82 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (5 mL). Compound A3 (0.5 g, 1.95 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. Benzyl bromide (235 μL, 1.97 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-benzyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A4) (0.54 g, 80% of theoretical) was obtained as a white solid by filtration.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:18][O:17][C@@H:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[CH2:22][OH:23]>ClCCl>[CH:19]1([C@@H:16]2[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[C@H:14]([CH2:22][OH:23])[CH2:15]2)[CH2:21][CH2:20]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Benzoyl isothiocyanate (0.540 mL, 4.02 mmol) was added drop-wise to a solution of rel-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C20) (1.20 g, 4.23 mmol) in dichloromethane (45 mL). After the reaction mixture had stirred at room temperature for 15 hours, it was partitioned between aqueous hydrochloric acid (0.1 M, 20 mL) and dichloromethane (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (25 mL) and with saturated aqueous sodium chloride solution (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 45% ethyl acetate in heptane) provided the product as a white solid. Yield: 1.69 g, 3.78 mmol, 89%. LCMS m/z 447.2 [M+H+]. 1H NMR (400 MHz, CD3CN) δ 11.64 (br s, 1H), 9.28 (br s, 1H), 7.89-7.93 (m, 2H), 7.64-7.69 (m, 1H), 7.52-7.58 (m, 2H), 7.44-7.58 (br m, 1H), 6.86-6.99 (m, 2H), 3.48-3.86 (br m, 2H), 3.35-3.47 (m, 1H), 3.01 (ddd, J=11.3, 7.6, 2.7 Hz, 1H), 2.89-3.0 (br m, 1H), 2.3-2.6 (br m, 1H), 1.96-2.03 (m, 1H), 1.7-1.9 (br m, 1H), 0.90-1.00 (m, 1H), 0.44-0.53 (m, 2H), 0.34-0.40 (m, 1H), 0.26-0.31 (m, 1H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]([F:23])[CH3:22].C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>O1CCCC1.C1COCC1.C1COCC1.Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[C:16]([F:20])[C:15]=1[CH:21]([F:23])[CH3:22]
Reactant: CC(F)c1c(F)cccc1Cl
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: -78 °C
Yield: 94 %

Procedure:
A 2.5 M solution of n-butyllithium (13 mL, 33 mmol) was added to a stirred solution of diisopropylamine (5.0 mL, 35 mmol) in tetrahydrofuran THF (50 mL) at −78° C. The resulting colorless solution was stirred at −78° C. for 20 m, warmed to 0° C. for 20 m, and then cooled back to −78° C. for 20 m. A solution of 1-chloro-3-fluoro-2-(1-fluoroethyl)benzene (4.8 g, 27 mmol, 1.0 equiv) in THF (20 mL) at −78° C. was transferred to the base solution via cannula. The resulting dark brown solution was stirred at −78° C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.3 mL, 41 mmol, 1.5 equiv) was added and the brown solution was slowly warmed to 23° C. over 20 h. The reaction mixture was diluted with 0.1M hydrochloric acid (300 mL) and extracted with dichloromethane three times. The combined organic layers were dried, filtered and concentrated by rotary evaporation to afford the title compound as a brown oil that solidified into a semi-solid upon standing (7.7 g, 94% yield). 1H NMR (300 MHz, CDCl3) δ 7.62 (m, 1H), 7.17 (m, 1H), 6.13 (dq, 1H, J=6, 46 Hz), 1.75 (ddd, 3H, J=1, 7, 23 Hz), 1.36 (s, 12 H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][O:10][CH2:11]Cl.C(OCC)(=O)C>CN(C=O)C>[CH3:9][O:10][CH2:11][O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1
Reactant: COCCl
Reactant: Cc1cccc(O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part A. Sodium hydride dispersion in mineral oil (5.05 g, 50% w/w, 105 mmol) was washed with hexane and dried under vacuum. DMF (100 mL) was added, the slurry was cooled to 0° C., and treated with a solution of m-cresol (10 mL, 95.6 mmol) in DMF (20 mL). The resulting mixture was allowed to stir for 1 h, then was treated with chloromethyl methyl ether (8.00 mL, 105 mmol) by syringe. The mixture was stirred overnight, then poured into ethyl acetate (200 mL). This was washed with water (3×200 mL) and brine (100 mL), and the aqueous phases were back-extracted in sequence with ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The oily product was purified by elution through a plug of silica gel with 10:90 ethyl acetate-hexane. Evaporation then afforded the pure product, 3-(methoxymethoxy)toluene, as an oil (13.93 g, 91.5 mmol, 96%). TLC RF 0.46 (10:90 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.17 (1H, t, J=7.7 Hz), 6.86-6.81 (3H, m), 5.17 (2H, s), 3.48 (3H, s), 2.33 (3H, s). MS (H2O-GC/Ms): m/e 153 (60), 121 (100).