Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[CH:57][C:56]([NH2:59])=[N:55]1>CN(C)C=O>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][N:54]1[CH:58]=[CH:57][C:56]([NH:59][C:8]([C:7]2[C:6]([F:11])=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[O:10])=[N:55]1
Reactant: O=C(O)c1c(F)cncc1F
Reactant: Nc1ccn(Cc2ccc(Cl)cc2Cl)n1
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: CN(C)C=O
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2Cl)n1)c1c(F)cncc1F
Reaction time: 0.08 h
Yield: 114.8 %

Procedure:
To a solution of 3,5-difluoro-4-pyridinecarboxylic acid (15.9 mg, 0.1 mmol, Frontier Scientific) in dimethylformamide (0.1 ml) was added HATU (38 mg, 0.1 mmol) in dimethylformamide (0.2 mL), followed by N,N-diisopropylethylamine (0.050 ml, 0.286 mmol) and the resulting solution left for 5 min. Finally, a solution of 1-[(2,4-dichlorophenyl)methyl]-1H-pyrazol-3-amine (24.2 mg, 0.01 mmol, ChemCollect GmbH) in N,N-dimethylformamide (0.1 ml) was added and the resulting solution shaken for 10 min. The solution was then left to stand for 16 h at ambient temperature after which the solvent was removed. A 1:1 mixture of dimethylsulphoxide:methanol (0.6 ml) was added and the solution purified by MDAP on SUNFIRE C18 column (Method D). The appropriate fraction was concentrated in vacuo then under nitrogen flow to give the title compound (4.4 mg);
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1.[I:13][CH3:14]>C(O)C>[I-:13].[CH3:14][N+:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][N:4]=2)[CH:8]=1
Reactant: CI
Reactant: Cc1cnc(-c2cccnc2)o1
Solvent: CCO
Product: Cc1cnc(-c2ccc[n+](C)c2)o1
Product: [I-]

Procedure:
5 g of 3-(5-methyloxazol-2-yl)-pyridine prepared as indicated in Chimica Therap 4, 437 (1973) is dissolved in 50 cm3 of ethanol, 3 cm3 of iodomethane is added and the whole is heated under reflux for 10 hours. After cooling and decanting, ether is added, and after filtering, 8.68 g of product is obtained. M.p.=147°-148° C., after crystallization from ethanol.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18](O)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26](=[O:29])([O-])[O-].[K+].[K+].[C:32](OC)([CH3:35])([CH3:34])C>CN1CCCC1=O>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:29][CH2:26][CH2:4][CH2:5][N:6]4[CH2:35][CH2:32][CH2:34][CH2:7]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: COC(C)(C)C
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCCC1
Temperature: 80 °C

Procedure:
To a solution of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol (2.5 g) in 1-methyl-2-pyrrolidinone (25 ml) and methyl tert-butyl ether (1.8 ml) was added potassium carbonate (815 mg). The mixture was degassed by holding under vacuum and letting down with nitrogen. This was carried out five times. The mixture was heated to 80° C. and 4-azoniaspiro[3,4]octane bromide (1.75 g) was added. The mixture was maintained at 80° C. for 3.5 hours. To the hot mixture was added water (27 ml) over 2 hours. The mixture was cooled to 64° C. and the solid filtered. The solid was washed with 1:1 v/v 1-methyl-2-pyrrolidinone/water (5 ml) and then water (4×5 ml). The solid was dried in a vacuum oven to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42]>>[ClH:1].[CH3:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reactant: COCCOCCBr
Agent: Cl
Product: COCCOCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)CNC2(c3cccc(C(C)C)c3)CCCCC2)c1
Yield: 52 %

Procedure:
Using methods analogus to those previously described, compound 11 (0.4 mmol) is reacted with 1-bromo-2-(2-methoxyethoxy)ethane to afford the title compound 60 ( 0.21 mmol, 52%) as a hygroscopic white solid: 1H NMR (CDCl3) δ 9.4 (br, 1H), 8.5 (br, 1H), 8.32 (br, 1H), 7.54 (s, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 6.56 (s, 1H), 6.47 (m, 2H), 4.34 (v br, water H), 4.1 (m, 4H), 3.83 (m, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 3.38 (s, 3H), 2.96 (hept, J=7 Hz, 1H), 2.8-2.6 (m, 5H), 2.4-2.2 (m, 3H), 2.15 (s, 3H), 1.80 (m, 2H), 1.6 (m, 1H), 1.5-1.3 (m, 3H), 1.27 (d, J=7 Hz, 6H); MS (CI) m/z 559.5 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]([C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH:15]=1)(C)[C:10]([O-])=[O:11])C>C1COCC1>[O:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([CH:9]([CH3:7])[CH2:10][OH:11])=[CH:15]1
Reactant: CCC(C)(C(=O)[O-])c1coc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(-1-benzofuran-3-yl)propanoate (1.09 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4, filtered and concentrated. The product, 2-(1-benzofuran-3-yl)-1-propanol, was obtained as a white oil pure enough to be taken to the next step without purification. Yield: 700 mg (79%); (M+H): 177.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:41]([N:44]([CH3:55])[C:45]1[S:46][C:47]2[CH:53]=[C:52]([NH2:54])[CH:51]=[CH:50][C:48]=2[N:49]=1)([CH3:43])[CH3:42].CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH:41]([N:44]([CH3:55])[C:45]1[S:46][C:47]2[CH:53]=[C:52]([NH:54][C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:16][CH:15]=3)=[O:14])[CH:51]=[CH:50][C:48]=2[N:49]=1)([CH3:43])[CH3:42]
Reactant: CC(C)N(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Yield: 51.7 %

Procedure:
Prepare according to Method A, using 4-(4-fluorophenyl)benzoic acid (253 mg, 1.17 mmol), HATU (451 mg, 1.19 mmol), N2-Isopropyl-N2-methyl-benzothiazole-2,6-diamine (200 mg, 0.904 mmol), DIEA (520 μL, 2.99 mmol), and a chromatography gradient of MeOH in CH2Cl2 (0-5%) to afford the title compound (196 mg, 52%). mass spectrum (m/e): 420.0 [M+H], 418.0 [M−H]. 1H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 8.27 (d, 1H, J=2.2 Hz), 8.06 (d, 2H, J=8.4 Hz), 7.85-7.78 (m, 4H), 7.56 (dd, 1H, J=8.8, 2.2 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.37-7.31 (m, 2H), 4.34 (m, 1H), 2.98 (s, 3H), 1.23 (d, 6H, J=6.6 Hz).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1C[N@@]1S(C1C=CC=C([C:34]([F:37])([F:36])[F:35])C=1)(=O)=O>>[F:35][C:34]([F:37])([F:36])[C:7]1[CH:6]=[C:5]([S:8]([NH:11][C@H:12]([CH2:14][C:15]#[C:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH3:13])(=[O:9])=[O:10])[CH:4]=[CH:3][CH:2]=1
Reactant: CC1C[N@@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)CC#C[Si](C)(C)C)cc1
Agent: CC1C[N@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Product: C[C@@H](CC#C[Si](C)(C)C)NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
Proceeding as described for (51), but using (S)-2-methyl-1-(3-(trifluoromethyl)-benzenesulfonyl)aziridine afforded (S)-3-(trifluoromethyl)-N-(5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide (52). MS (m/z): 364.1 (M+H) (Calc'd for C15H20F3NO2SSi: 363.47).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: Fc1ccc(-n2cc(Br)cn2)cc1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(-c4ccc(F)cc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-Bromo-1-(4-fluoro-phenyl)-1H-pyrazole.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH3:14])[C:7]=1[C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:5]>CO>[CH2:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH3:14])[C:7]=1[C:15](=[O:21])[C:16]([NH:2][NH2:3])=[O:17])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Solvent: O
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Temperature: 2 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a 100 ml volume four-necked flask, methanol (22.91 g) and hydrazine hydrate (1.93 g) were added at room temperature, and cooled. Ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate (9-a) (5.01 g) diluted with methanol (10.02 g) was added dropwise at 1° C. over 5 minutes. The resulting mixture was stirred at 2° C. for 4 hours, then the mixture was filtered. The resulting filtrate was concentrated, added tert-butyl methyl ether (41 g), and washed with brine (14 g). The resulting organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel: 40 g, hexane:ethyl acetate=1:1) to gave 1.88 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]=4)=[O:22])=[CH:16][CH:15]=3)[CH:9]=[C:10]([C:11](O)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[N:25]=4)=[O:22])=[CH:18][CH:19]=3)[CH:9]=[C:10]([C:11]([NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C(=O)O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Reactant: NCC(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C(=O)NCC(F)(F)F)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of 4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (30.0 mg, 0.066 mmol), 2,2,2-trifluoroethylamine (32.5 mg, 0.33 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (58.0 mg, 0.13 mmol), and 4-methylmorpholine (13.3 mg, 0.13 mmol) in DMF (2 mL) was stirred at rt overnight. The crude reaction mixture was purified directly by HPLC using a gradient of 30-90% MeCN in water to afford 16.4 mg (36%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.88 (s, 1H), 9.73 (s, 1H), 9.40 (t, J=6.6 Hz, 1H), 8.34 (bs, 1H), 8.18 (s, 1H), 8.05 to 7.98 (m, 2H), 7.58 (d, J=8.6 Hz, 2H), 7.51-7.49 (m, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.24 (s, 1H), 5.94 (bs, 1H), 4.33-4.24 (m, 2H); MS [M+H]+=539.0; LCMS RT=3.24 min.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1([C@@H:19]2[CH2:23][O:22][C:21](=[O:24])[NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:24]=[C:21]1[N:20]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[C@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:23][O:22]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Product: CCOC(=O)c1ccc(N2C(=O)OC[C@H]2c2ccccc2)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using ethyl 4-iodobenzoate (1.7 mL) and (R)-(−)-4-phenyloxazolidin-2-one (2 g), the title compound (4 g) was obtained.
Reaction SMILES: C(Cl)(Cl)=O.[CH3:5][O:6][C:7](=[O:19])[C@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:9][CH:10]=O.CN1CCOCC1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:19])[CH:8]([N+:9]#[C-:10])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC=O
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: [C-]#[N+]C(Cc1ccccc1)C(=O)OC

Procedure:
A solution of phosgene (5.2 g, 0.052 mole) in dry methylene chloride (45 ml) is added dropwise to a stirred solution of N-formylphenylalanine methyl ester (10.0 g, 0.048 mole) and 1-methylmorpholine (13 g, 0.125 mole) in dry methylene chloride (25 ml) at -30° C. After completion of the addition the filtrate is concentrated under reduced pressure at room temperature. Benzene is added to the residue followed by filtration and concentration of the resulting solution. The residue is distilled to afford the title compound as a yellow oil, b.p. 97° C/0.3 mm, νmaxCHCl3 2150, 1746, 1595, 1578, 1489, 694 cm-1.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]([C:11]1[N:12]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[S:14][CH:15]=1)=[O:10])[CH3:7].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>O1CCCC1>[CH2:6]([O:8][C:9]([C:11]1[N:12]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[S:14][C:15]=1[CH:28]([OH:29])[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[O:25][CH3:24])=[O:10])[CH3:7]
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: COc1ccccc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC(=O)OC(C)(C)C)sc1C(O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.3 %

Procedure:
Butyl lithium (2.5 M, 53 mL, 132 mmol) was slowly added to a solution of 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid ethyl ester (16.4 g, 60 mmol) in anhydrous tetrahydrofuran (250 mL) at −78° C. under a nitrogen atmosphere. A solution of 2-methoxybenzaldehyde (10.89 g, 79.99 mmol) in tetrahydrofuran (50 mL) was then added dropwise at −78° C. The mixture was warmed slowly to room temperature and stirred for 15 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (500 mL). The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was then purified by column chromatography to yield the pure product (12 g, 29 mmol, 48%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][C@:28]1([CH2:42][O:43][CH3:44])[CH2:32][N:31]([C@@H:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:34])[C:30](=[O:41])[CH2:29]1>ClCCl>[Br:5][CH2:1][CH2:27][C@:28]1([CH2:42][O:43][CH3:44])[CH2:32][N:31]([C@@H:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:34])[C:30](=[O:41])[CH2:29]1
Reactant: BrC(Br)(Br)Br
Reactant: COC[C@]1(CCO)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC[C@]1(CCBr)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
Carbon tetrabromide (3.58 g, 10.8 mmol) and triphenylphosphine (2.83 g, 10.8 mmol) were sequentially added to a solution of (4R)-4-(2-hydroxyethyl)-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (2.85 g, 10.3 mmol) in dichloromethane (30 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred for 10 minutes. The mixture was heated to room temperature and stirred for 24 hours, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=2:1→1:1→1:2) to give 2.07 g (59%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Product: CC(=O)Oc1ccc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of 10 g. 4-hydroxy-3-chlorobenzoic acid and 50 ml. of acetic anhydride is refluxed for two hours. Excess acetic anhydride is distilled under vacuum and the residue diluted and stirred with a mixture of methanol (100 ml.) and water (20 ml.) at about 50° for 30 minutes. The mixture is then reduced to low volume under vacuum, water added and the precipitated crystals filtered. Recrystallization from toluene gives 6.5 g. (52% yield) m.p. 162°-163° C.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].Cl>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Temperature: 120 °C
Yield: 85.6 %

Procedure:
To a suspension of 27 (0.400 g, 2.60 mmol) [G. B. Evans, R. H. Furneaux, et. al J. Org. Chem., 2001, 66, 17, 5723-5730] in diphenylether (25 ml) was added 2-fluoro-4-nitrophenol (614 mg, 3.90 mmol) and HCl (2N in Et2O) (0.19 ml, 3.90 mmol). The reaction mixture was heated at 120° C. for 4 hours, cooled to room temperature and concentrated under reduced pressure, to afford title compound 243 (610 mg, 86% yield) as a black solid. MS (m/z): 274.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@H:3](OS(C(F)(F)F)(=O)=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.Cl.[NH2:31][C@@H:32]([CH2:36][S:37]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)(=[O:39])=[O:38])[C:33]([OH:35])=[O:34]>C(Cl)Cl.CCOCC>[N:40]1([S:37]([CH2:36][C@H:32]([NH:31][C@@H:3]([C:4]2[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=2)[C:2]([F:1])([F:19])[F:20])[C:33]([OH:35])=[O:34])(=[O:39])=[O:38])[CH2:41][CH2:42][O:43][CH2:44][CH2:45]1
Reactant: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Reactant: N[C@@H](CS(=O)(=O)N1CCOCC1)C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)[C@H](CS(=O)(=O)N1CCOCC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
To a solution of trifluoromethanesulfonic acid-2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethyl ester (0.511 g, 88% pure, 1.38 mmol) in CH2Cl2 (5 mL) at rt was added DIPEA (Aldrich, 0.74 mL, 4.24 mmol) followed by the solid HCl salt of 2(R)-amino-3-(morpholin-4-sulfonyl)-propionic acid (0.292 g, 1.06 mmol) in small portions over 2 min. The initially homogeneous orange-brown solution became heterogeneous within minutes and was allowed to stir overnight at rt. The reaction mixture was then diluted with Et2O and quenched with 1M NaOH. The pH 14 aqueous layer was separated, washed with Et2O and acidified to pH 2 with 12M HCl. The aqueous layer was then extracted with Et2O. The combined Et2O extractions of the acidic solution were washed with brine and dried over anhydrous Na2SO4. Following concentration in vacuo, 0.034 g (7.7%) of 3-(morpholin-4-sulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionic acid was obtained as a colorless film.
Reaction SMILES: [CH2:1]=O.[N:3]1([C:9]([S:11][CH3:12])=[S:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.C(Cl)(Cl)Cl>[OH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:1][N:6]1[CH2:7][CH2:8][N:3]([C:9]([S:11][CH3:12])=[S:10])[CH2:4][CH2:5]1
Reactant: Oc1ccccc1
Reactant: C=O
Reactant: CSC(=S)N1CCNCC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CSC(=S)N1CCN(Cc2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
In 10 ml of ethanol was dissolved 0.86 g of 35% formalin. To the solution was dropwise added under chilling with ice a solution of 2.35 g of methyl 1-piperazinecarbodithioate in 4 ml of ethanol. The mixture was then stirred for 30 min. at room temperature. The mixture was refluxed overnight under heating after addition of a solution of 2.82 g of phenol in 4 ml of ethanol under chilling with ice and subsequent stirring at room temperature for 3 hours. The reaction mixture was cooled to room temperature. A half amount of the solvent was distilled off under reduced pressure. To the residue was added 5 ml of ether to precipitate crystals. The crystals were collected by filtration and washed with 15 ml of ether to give 1.63 g of crude crystals of the desired compound. The crude crystals were then dissolved in chloroform. To the chloroform solution was added ethanol in twice amount of the amount of the chloroform. Precipitated crystals were collected by filtration to give 0.95 g of the desired compound as a white crystalline product, m.p. 147° C., yield 33.4%.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH:24]([CH3:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:15]([Br:19])=[CH:16][C:17]=3[CH2:18][CH:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].[Cl:36]CCl>>[ClH:36].[Br:19][C:15]1[C:14]([C:20]([F:22])([F:23])[F:21])=[CH:13][C:12]2[N:11]3[C@H:24]([CH3:26])[CH2:25][NH:8][CH2:9][C@H:10]3[CH2:18][C:17]=2[CH:16]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC2Cc3cc(Br)c(C(F)(F)F)cc3N12
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC[C@H]2Cc3cc(Br)c(C(F)(F)F)cc3N21
Product: Cl
Reaction time: 1 h

Procedure:
8-Bromo-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (0.35 g, 0.8 mmol) were dissolved in dichloromethane (12 mL) and trifluoroacetic acid was added (3 mL). The mixture was stirred for 1 h, added to 1 N sodium hydroxide solution (50 mL) and extracted with dichloromethane (3×40 mL). Organic phases were pooled, washed with brine, dried with MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel (dichloromethane/methanol 19:1) yielded the title compound as a colorless oil which was precipitated as HCl salt from diethylether (0.2 g; 73%). ISP-MS: m/e=335.2, 337.2 (M+H+), αD20=−48.6.
Reaction SMILES: [C:1]1([CH:7](O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(F)(F)[F:17])C=CC=CC=1>C(Cl)Cl>[F:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: CC(O)c1ccccc1
Reactant: FC(F)(F)c1ccccc1
Agent: *CC*
Solvent: ClCCl
Product: CC(F)c1ccccc1
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
Under a protective gas atmosphere 0.83 g (6.8 mmol) of 1-phenylethanol is added dropwise in the course of 5 min to a solution of 2.32 g (7.56 mmol) of i-Prop2N═CHF+HF2−.HNEt3+.HF2− in 10 ml of CH2Cl2 in a polyethylene container. The mixture is stirred for several hours at 20° C. and the conversion rate is analysed by 19F-NMR (reference: PhCF3). After 2.5 h, 81% of 1-fluoroethylbenzene is obtained, and after a stirring time of 24 h, 96% of product is obtained.