Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)=O>>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccccc1N
Product: c1ccc(-c2nc3ccccc3[nH]2)nc1
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A 2 liter 3-neck round-bottom flask fitted with a reflux condenser, N2 (g) inlet, mechanical stirrer, and heating mantle was charged with 88.7 g of 1,2-phenylenediamine, 100.0 g of picolinic acid, and 500 g of polyphosphoric acid. The resulting slurry was slowly heated (over a period of approximately three hours) to 210° C. under a positive nitrogen atmosphere, with mechanical stirring. The reaction mixture was heated for an additional six hours while maintaining the temperature between 200°-220° C. The reaction mixture was cooled to below 100° C. and cautiously poured into 2 liters of hot distilled water. The resulting slurry was stirred for approximately one hour, cooled and the pH adjusted to approximately 6-7 using concentrated aqueous NaOH. The slurry was stirred for an additional hour, cooled, and filtered. The precipitate was thoroughly washed with distilled water and dried.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]([OH:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5](=[O:14])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1O)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([N:4]1[CH2:15][CH:16]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:24][C:7]2[CH:8]=[CH:9][C:10]([I:12])=[CH:11][C:6]=2[C:5]1=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(O)Cc1ccccc1)C(=O)c1cc(I)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To a magnetically stirred solution of N-allyl-N-(2-hydroxy-5-iodobenzoyl)-2-hydroxy-3-phenylpropylamine (12.05 grams, 0.027 mol) in 100 mL THF was added triphenylphosphine (7.24 grams, 0.027 mol), and diethyl azodicarboxylate (4.7 grams, 0.027 mol). The mixture was heated to reflux overnight, allowed to cool to room temperature, and concentrated in vacuo. the resulting residue was dissolved in ethyl acetate (10 mL) and diluted with diethyl ether. The solids that form were filtered and the mother liquor was concentrated in vacuo. The yellow oil was purified by column chromatography (SiO2, using 15% diethyl ether/85% hexane to 1:1 diethyl ether/hexane as the eluting solvent gradient, Rf(product, 1:1 Et2O/heaxane)=0.64) to yield 4.31 grams (38%) of 2-allyl-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.10 (1H, d, 4JHH =2 Hz, C9-H), 7.69 (1 H, dd, 4JHH =2 Hz, 3JHH =9 Hz, C7-H), 7.4-7.2 (5H, m, C6H5), 6.76 (1H, d, 3JHH =9 Hz, C6-H), 5.79 (1H, ddt, 3JHH =17 Hz, 3JHH =11 Hz, 3JHH =6 Hz, CH2CH=CH2), 5.2-5.0 (2H, m, CH=CH2), 5.71 (1H, m, CHOH), 4.31 (1H, ddt, 2JHH =15 Hz, 3JHH =6 Hz, 4JHH =1 Hz, NCHHCH=CH2), 4.00 (1H, ddt, 2JHH =15 Hz, 3JHH 6 Hz, 4JHH =1 Hz, NCHHCH=CH2), 3.34 (1H, dd, 2JHH =16 Hz, 3JHH =5.1 Hz, C3-H), 3.25 (1H, dd, 2JHH =16 Hz, 3JHH =4.2 Hz, C3-H), C3-H), 3.09 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh), 2.73 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh). 13C NMR (CDCl3) 166.9, 152.7, 141.4, 139.6, 136.5, 132.6, 129.8, 129.1, 128.8, 127.0, 124.6, 118.4, 86.7, 84.7, 50.4, 48.9, 38.9. IR (NaCl, cm-1) 1641, 1589, 1463, 1430, 1264, 1217, 699.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2′-fluoro-4′-methoxyacetophenone (4.45 g, 26.5 mmol) in THF (50 ml) at 0° C., a solution of 2.4 M MeMgBr (11.6 mmol, 27.8 mmol) was added. The mixture was stirred at 0° C. and then room temperature for 4 h. The reaction was quenched with saturated ammonium chloride solution. The organic was extracted with ethyl acetate (3×50 ml). The combined ethyl acetate layers were washed with brine and dried over sodium sulfate. The resulting alcohol was obtained as an oil after flash column using EtOAc:hexane=2:8 as the elute.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH:17]3[CH2:19][CH:14]2[CH2:15][N:16]3[CH:20]([CH3:22])[CH3:21])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:6](=[O:31])[N:7]2[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30].[F:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1B(O)O>>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[N:7]1[C:8]2[C:3](=[C:2]([C:45]3[CH:44]=[CH:43][C:42]([F:41])=[CH:47][C:46]=3[F:48])[CH:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH:17]4[CH2:19][CH:14]3[CH2:15][N:16]4[CH:20]([CH3:21])[CH3:22])[CH:9]=2)[CH2:4][N:5]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C:6]1=[O:31]
Reactant: COc1ccc(CN2Cc3c(Br)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: OB(O)c1ccc(F)cc1F
Product: COc1ccc(CN2Cc3c(-c4ccc(F)cc4F)cc(CN4CC5CC4CN5C(C)C)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-bromo-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (EXAMPLE AAA16, STEP C) and 2,4-difluorobenzene boronic acid as described in EXAMPLE AAA16, STEP D. 1H NMR (CDCl3, 500 MHz): δ 1.03 (s, 3H), 1.08 (s, 3H), 1.59 (brs, 2H), 2.40 (m, 2H), 2.56 (brs, 1H), 2.83 (m, 1H), 2.90 (brs, 1H), 3.15 (s, 1H), 3.58 (abq, 3H, J=14.5 Hz), 3.81 (s, 3H), 4.20 (brs, 2H), 4.58 (brs, 2H), 6.23 (s, 1H), 6.85 (m, 3H), 6.91 (m, 2H), 7.14 (q, 1H, J=7.1 Hz), 7.23 (d, 2H, J=8.5 Hz), 7.39 (t, 1H, J=8.0 Hz), 7.54 (d, 2H, J=8.1 Hz). MS (API-ES+): 677 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([C:10](=[O:15])N(OC)C)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH3:9])[C:10](=[O:15])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
In a round-bottomed flask, [(R)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (3.00 g, 12.9 mmol) was dissolved in THF (100 ml). The solution was cooled to −16° C. (NaCl/ice bath) and methylmagnesium bromide (3.0 M in diethyl ether, 12.0 ml, 36.0 mmol) was added dropwise over 20 min. After the addition, the reaction mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was cooled to 0° C., quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 2.21 g (91%) of ((R)-1-methyl-2-oxo-propyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOC(C)=O>[ClH:20].[Cl:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Clc1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the ester from step (a) above (2.98 g, 10 mmol) in MeOH (5 mL) was added saturated solution of hydrogen chloride in EtOAc (50 mL) and the mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo, and the residue was washed with EtOAc and dried in the air to provide the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 198 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][OH:19])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)O)cc2C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CO)cc2C1
Yield: 93 %

Procedure:
To a solution of 0.245 mmol of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid in 2 ml dry THF were added at room temperature 0.736 mmol borane dimethyl sulphide complex and the mixture was stirred over night. The mixture was diluted with EtOAc and washed with saturated Na2CO3 solution and brine. The aqueous layer was extracted with EtOAc. The combined organic layers were washed, dried over MgSO4 and filtered. Evaporation of the solvent gave 60 mg of a pale yellow oil (93%).
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][C:5]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)([OH:13])[C:4]=2[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:34][Si:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][O:38][CH2:39]Cl>C1COCC1>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]([CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:42])([CH3:41])[CH3:34])[CH2:6][C:5]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)([OH:13])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)NCC(O)(c2ccc3ccccc3c2)c2cc(Cl)sc21
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1CC(O)(c2ccc3ccccc3c2)c2cc(Cl)sc2S1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 6-chloro-4-(2-naphthyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazin-4-ol 1,1-dioxide (0.235 g, 0.642 mmol) in THF (5.2 mL) at −78° C. was added 1.00 M Lithium hexamethyldisilazide in THF (0.771 mL, 0.771 mmol). The reaction mixture was stirred at −78° C. for 30 min, and [β-(trimethylsilyl)ethoxy]methyl chloride (0.341 mL, 1.93 mmol) was added at the same temperature. The mixture was stirred for 1 h at −78° C. and raised to rt. After stirring at rt for 30 min, the mixture was quenched by sat. NH4Cl, extracted with EA, dried and evaporated. The residue was purified by Isco silica gel chromatography (24 g cartridge), EA in hex, 0-30% using solid load to give the title compound (0.140 g, 42%). LCMS (FA) ES−: 494, 496. 1H NMR (400 MHz, DMSO) δ 7.95-7.92 (m, 4H), 7.55-7.52 (m, 2H), 7.32-7.29 (m, 1H), 6.77 (s, 1H), 6.74 (s, 1H), 4.91 (d, 1H), 4.64 (d, 1H), 4.20 (d, 1H), 3.95 (d, 1H), 3.52-3.47 (m, 2H), 0.85-0.76 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:33][C:34]([F:45])([F:44])[CH2:35]OS(C(F)(F)F)(=O)=O>C1COCC1>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:35][C:34]([F:45])([F:44])[F:33])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1csc(C2CCN(CC(F)(F)F)CC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reaction time: 2 h
Yield: 68.9 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-159) (0.072 g, 0.21 mmol) was dissolved in dry THF (5 mL) and DIPEA (0.66 mmol) was added followed by 2,2,2-trifluoroethyltrifluoromethanesulphonate (0.26 mmol) and the resulting mixture stirred for 2 hours. 2,2,2-Trifluoroethyltrifluoromethanesulphonate (0.26 mmol) was added and the mixture refluxed overnight. The solvent was evaporated and the resulting gum was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.06 g). LCMS m/z 415.13 [M+H]+ RT=12.16 min (Analytical Method 2).
Reaction SMILES: [C:1]([C@:4](CO)([OH:25])[C@:5](C(=O)C)([OH:21])[C@:6](C(=O)C)([OH:17])[C@@:7](C(=O)C)([OH:13])[C:8]([CH2:10][CH:11]=[CH2:12])=[O:9])(=[O:3])C>[OH-].[Na+]>[CH2:10]([C:8]([C@@H:7]([C@H:6]([C@H:5]([C@@H:4]([CH2:1][OH:3])[OH:25])[OH:21])[OH:17])[OH:13])=[O:9])[CH:11]=[CH2:12]
Reactant: C=CCC(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@](O)(C(C)=O)[C@](O)(CO)C(C)=O
Agent: [Na+]
Agent: [OH-]
Product: C=CCC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reaction time: 2 h

Procedure:
Compound 1 (23 g) was dissolved in 4N NaOH solution (100 ML) and stirred for 2 hr. The reaction mixture was extracted with ether. The aqueous layer was acidified with Dowex-H resin. The resin was removed by filtration and the filtrate was lyophilized to give the deprotected derivative 2 as a white powder. This was recrystallized in ethyl acetate-methanol (7:3) to give crystals (7.0 g). 1N NMR (CD3OD): δ8.2-8.90, m, 1H, CH2CH═CH2; 5.12-5.09, dd, 2H, CH2CH═CH2;3.99-4.01, m, 1H, H-1; 3.80-3.84, m, 1H, H-2; 3.87-3.62, mm, 3H, H,4,5,6: 13C NMR (CD3OD): 136.73, 116.86, 75.66, 74.02, 71.91, 70.11, 70.00, 61.97, 31.03: [α]D=+106.45 (c 1.03, methanol).
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=2>C1COCC1.CO>[CH3:1][N:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=2
Reactant: CCOC(=O)COc1cccc2c1N(C)C(=O)CO2
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)COc1cccc2c1N(C)CCO2
Temperature: 27 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
A solution of ethyl 2-((4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)oxy)acetate (100 mg, 0.377 mmol) in anhydrous THF (3 mL) was cooled to 0° C. and BH3-Me2S (0.1 mL) added. The solution was stirred at 27° C. for 6 h, diluted with methanol and concentrated. The residue was partitioned between ethyl acetate (30 mL) and water (20 mL), the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC. (72 mg, yield 76%) MS (ESI+) e/z: 252.2 [M+1]+. 1H NMR (CDCl3, 400 MHz), δ ppm: 6.87-6.76 (m, 1H), 6.62-6.52 (m, 1H), 6.40-6.28 (m, 1H), 4.70 (s, 2H), 4.34-4.22 (m, 2H), 4.18-4.06 (m, 2H), 3.21-3.07 (m, 2H), 2.99-2.85 (m, 3H), 1.33-1.25 (m, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)#[CH:12].N>>[N:6]1[CH:5]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[O:1][N:2]=2)[CH:9]=[N:8][CH:7]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1ccc(C#N)cc1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cncnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 4-ethynylbenzonitrile (Aldrich, 64 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ7.99 (s, 1H), 8.10 (s, 4H), 9.34 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4]O.CN(C1C=CC=CN=1)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][CH:2]1[CH2:3][CH2:4][O:7][C:6]1=[O:8])(=[O:20])[CH3:19]
Reactant: N[C@@H](CCO)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Product: CC(=O)NC1CCOC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
L-Homoserine (2 mol) was suspended in 900 ml of acetic anhydride and admixed with a spatula tip full of dimethylaminopyridine (DMAP). It was slowly heated to 60° C. After approximately 1 hour, the temperature rapidly increased to 100° C. Subsequently the reaction mixture was stirred at 80° C. for 90 minutes and concentrated to dryness under vacuum. The resultant yellow oil was taken up in isopropanol (600 ml) and allowed to stand overnight at 0° C. The resultant crystals were filtered off, washed with cold isopropanol and dried under vacuum. The yield was 60% N-acetyl-2-amino-4-butyrolactone isolated, the purity 99% (according to HPLC).
Reaction SMILES: Cl.O1CCOCC1.CN(C)S([N:13]1[CH:17]=[CH:16][C:15]([C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)([NH:20]S(C(C)(C)C)=O)[CH3:19])=[N:14]1)(=O)=O>CO>[Cl:33][C:29]1[CH:28]=[C:27]([C:18]([NH2:20])([C:15]2[CH:16]=[CH:17][NH:13][N:14]=2)[CH3:19])[CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)S(=O)(=O)n1ccc(C(C)(NS(=O)C(C)(C)C)c2cccc(Cl)c2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(N)(c1cccc(Cl)c1)c1cc[nH]n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
Hydrochloric acid 4 M in dioxane (19.79 mL, 79.15 mmol) was added to a solution of 3-[1-(3-chloro-phenyl)-1-(2-methyl-propane-2-sulfinylamino)-ethyl]-pyrazole-1-sulfonic acid dimethylamide (2.29 g, 5.28 mmol) in MeOH (5 mL) and the mixture was stirred at 80° C. in a sealed tube for 18 hours. The solvent was evaporated in vacuo. The residue was poured into NaHCO3 (aq. sat. solution) and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield rac-1-(3-chloro-phenyl)-1-(1H-pyrazol-3-yl)-ethylamine (1 g, 86% yield) as a pale yellow solid which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:27]([F:28])([F:29])[F:30])=[CH:20][C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc(C(F)(F)F)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-4-methoxybenzotrifluoride (55 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (56 mg, 70%/O). 1H NMR (CDCl3): 9.66 (dd, J=0.6, 2.1 Hz, 1H), 8.95 (s, 1H), 8.75 (dd, J=1.8, 4.8 Hz, 1H), 8.73-8.69 (m, 1H), 7.67 (s, 1H), 7.46-7.42 (m, 1H), 7.41-7.37 (m, 1H), 7.01 (d, J=8.4 Hz, 1H) 6.93 (s, 1H), 3.99 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[CH2:15]([NH2:17])[CH3:16].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C1COCC1>[CH2:15]([NH:17][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1)[CH3:16]
Reactant: Cc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCNc1nc2ccc(C)cc2cc1C=O
Temperature: 160 °C
Yield: 54 %

Procedure:
To a solution of 2-chloro-6-methylquinoline-3-carbaldehyde (1.0 g, 4.86 mmol) in dioxane (10 mL) in a 20 mL microwave vial was added ethylamine (4 mL, 70% in water) and the resulting mixture was heated at 160° C. under microwave irradiation for 45 min. After cooling to RT, the mixture was poured into a solution THF:1 N HCl=1:1 (25 mL) and stirred for 25 min at RT. The mixture was neutralized until pH=7 with a saturated solution of NaHCO3 and extracted with CH2Cl2 (50 mL). The organic layer was washed with H2O (3×30 mL), brine (30 mL), dried over Na2SO4, filtered and evaporated to give 2-(ethylamino)-6-methylquinoline-3-carbaldehyde RBO 35156 as a yellow solid (566 mg, 54% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:27]([C:30](OC(C)(C)C)=O)[NH:28]C)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:27]([CH3:30])[NH2:28])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(N)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-benzyl 3-(4-(benzyloxy)phenyl)-2-(N-(tert-butoxycarbonyl)-N′-methylhydrazinyl)propanoate (Compound XXVII-1) 491 mg (1.00 mmol) in dichloromethane 1 ml, trifluoroacetic acid 743 μl (10.0 mmol) was added and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate solution 50 ml. The organic phase was washed with water 50 ml and brine 50 ml. The organic phase was dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([O:25]CC)=[O:24])[CH:17]=[CH:16]3)=N1.CI.C1C[O:40]CC1>>[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:23]([OH:25])=[O:24])[CH:17]=[CH:16]2)([OH:5])=[O:40]
Reactant: CCCCCCC(C(=O)OCC)n1ccc2cc(-c3ccccc3C3=NC(C)(C)CO3)ccc21
Reactant: C1CCOC1
Solvent: CI
Product: CCCCCCC(C(=O)O)n1ccc2cc(-c3ccccc3C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[5-[2-(4,4-dimethyloxazolin-2-yl)phenyl]indole-1-yl]octanoate (0.174 mmoles, 80 mg) was dissolved in 1 ml THF. Methyl iodide (0.15 ml, 1.1 mmole) was added. After stirring overnight at room temperature, the solution was concentrated. The residue was dissolved in 7 ml of 2:1 MeOH:2N NaOH and heated at 90° C. for 24 hours. The reaction was cooled to 0° C. and washed with ether. The pH was adjusted to 1.0 using 2N HCL. The product was extracted with 20% EtOH in ethyl acetate. The organic layer dried and concentrated to yield 35 mg of 2-[5-(2-Carboxyphenyl)indol-1-yl]octanoic acid that solidified upon standing. (MS)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:15][C:16]1[C:21]([C:22]#N)=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14].[OH2:41]>C1(C)C=CC=CC=1.CO>[CH2:11]([O:15][C:16]1[C:21]([CH:22]=[O:41])=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Temperature: 25 °C

Procedure:
Diisobutyl aluminum hydride (1.0M in toluene, 3 mL, 3 mMol) was added in three portions over 26 hours (0 hours, 24 hours, 26 hours) to a solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile, Example 14, (0.42 gm, 1 mMol) in toluene (75 mL) and stirred at room temperature. Methyl alcohol (5 mL) was added dropwise followed by a solution of water (5 mL) in methyl alcohol (25 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a semi-solid. The products were separated and purified by silica gel chromatography. Example 29 Anal. Calc'd. C23H24NO4SF: C, 64.32; H, 5.63; N, 3.26. Found: C, 64.27; H, 5.59; N, 3.23. Example 30 Anal. Calc'd. C23H22NO4SF: C, 64.62; H, 5.19; N, 3.28. Found: C, 64.84; H, 5.39; N, 3.58.