Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:42]=[N:43][CH:44]=[CH:45][CH:46]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[N:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cccnn3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methylpyridazine-3-carboxamide
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[NH4+:16]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:16])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 5.00 g 3-fluoro-4-nitrobenzenesulfonyl chloride in 20 mL acetonitrile cooled in an ice bath was added dropwise 4.40 mL of a 30% ammonium hydroxide solution. After removal of the ice bath, stirring was continued for 30 min. at room temperature. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness to give 4.65 g (99%) of a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 2H), 7.89 (d, J=9.33 Hz, 1H), 7.92 (dd, J=10.23, 1.81 Hz, 1H), 8.14-8.21 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[I:14]Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:14])=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(Cl)ncc1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottom flask was charged with 2-chloro-4-amino pyridine (3.0 g, 23.34 mmol), sodium acetate (11.49 g, 140 mmol) and acetic acid (60 mL). To this iodine monochloride (3.98 g, 24.50 mmol) was added and the reaction mixture stirred at 60° C. for 2 h. The reaction was cooled to room temperature and quenched with 1N saturated sodium bis-sulfite solution and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was purified by silica gel flash chromatography using DCM-MeOH: 95-5. 2-Chloro-5-iodo-pyridin-4-ylamine was obtained as a white color solid. ESI-MS: m/z 255.0 (M+H)+
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][OH:24].[OH-].[K+]>O.O1CCCC1>[OH:24][CH2:23][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=2)[N:12]([CH3:5])[CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(CO)c(=O)c2ccc(C(F)(F)F)cc21
Reaction time: 3 h

Procedure:
Dimethyl sulphate (24.4 g.) was added over 5 minutes to a stirring solution of 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline (23.6 g.) and potassium hydroxide (16.3 g.) in a mixture of water (50 ml.) and tetrahydrofuran (50 ml.) at room temperature. After stirring for a further 3 hours at this temperature the solid product was collected. The filtrate was extracted with dichloromethane (3×200 ml.). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to give a second crop of the solid. The combined solids were purified by high pressure liquid chromatography over silica gel, eluting with isopropanol:dichloromethane 10:90 at a flow rate of 200 ml. per minute. The same solvent was used for applying the product to silica gel. This procedure gave the novel 3-hydroxymethyl-1-methyl-7-trifluoromethyl-4-quinolone, m.p. 172°-175°.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:33]4[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=4)[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]=34)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.S=[C:42]1[NH:46][C:45](=[O:47])[CH2:44][S:43]1.C(O)(=[O:50])C>>[C:14]12([C:24]3[CH:25]=[C:26]([C:33]4[CH:34]=[CH:35][C:36]([CH:37]=[C:44]5[S:43][C:42](=[O:50])[NH:46][C:45]5=[O:47])=[CH:39][CH:40]=4)[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]=34)[CH2:23][CH:18]3[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]3)[CH2:21]1)[CH2:15]2
Reactant: O=Cc1ccc(-c2cc3c(c(C45CC6CC(CC(C6)C4)C5)c2)OCO3)cc1
Reactant: O=C1CSC(=S)N1
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(-c3cc4c(c(C56CC7CC(CC(C7)C5)C6)c3)OCO4)cc2)S1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
A solution of toluene (100 mL), piperidine (100 μL), acetic acid (100 μL), 4-[3-(1-adamantyl)-4,5-methylenedioxyphenyl]-benzaldehyde (1.50 g, 4.16 mmol, see Example 1a) and 2-thioxo-4-thiazolidinone (0.554 g, 4.16 mmol) was heated at reflux overnight under an argon atmosphere. Within 20 minutes an orange-yellow solid formed. A Dean-Stark trap was attached and after 48 hours the reaction mixture was cooled to room temperature, and the resulting crystalline compound was filtered and washed with ethanol. The yellow solid was dried under high vacuum to afford 1.50 g (76%) of 4-[3-(1-adamantyl)-4,5-methylenedioxyphenyl]-benzylidene-2,4-thiazolidinedione, mp 337.5–338.5° (dec). 1H NMR (500 MHz; DMSO-d6): 1.75 (s, 6H), 2.05 (s, 9H), 6.05 (s, 2H), 7.07 (s, 1H), 7.22 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 13.6–13.9 (brs, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:8]=2)[NH:3]1.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([NH:31][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN
Reactant: O=c1cc(C(F)(F)F)c2cc(Cc3ccc(S(=O)(=O)Cl)cc3)ccc2[nH]1
Product: CCCCNS(=O)(=O)c1ccc(Cc2ccc3[nH]c(=O)cc(C(F)(F)F)c3c2)cc1
Yield: 91.2 %

Procedure:
4-(2-oxo-4-trifluoromethyl-1,2-dihydroquinolin-6-ylmethyl)benzenesulfonyl chloride (Preparation 1, 26 mg, 65 μmol) was reacted with an excess of n-BuNH2 (190 mg, 2600 μmol) by the same procedure used for Example 1. After reaction, the solvents were evaporated off under reduced pressure & the residue partitioned between EtOAc (10 mL) & 2 M HCl (3 mL). The organic phase was washed with H2O (2 mL), 1 M NaOH (3 mL), & brine (2 mL), before being dried (MgSO4). Filtration & solvent evaporation furnished the title compound (26 mg, 84%): δH ((CD3)2SO)=0.75 (t, 3H), 1.20–1.35 (m, 4H), 2.65 (m, 2H), 4.15 (s, 2H), 6.95 (s, 1H), 7.35–7.55 (m, 5H), 7.70 (d, 2H); m/z (ES+)=480.2 [M+H+MeCN]+.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].[H-].[Na+].Br[C:12]1[S:13][C:14]([Br:17])=[CH:15][N:16]=1>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[Br:17][C:14]1[S:13][C:12]2=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:1]=[CH:2][N:16]2[CH:15]=1
Reactant: Brc1cnc(Br)s1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2cc(Br)sc12
Reaction time: 2 h

Procedure:
Ethyl isocyanoacetate (0.9 ml, 8.2 mmol) was gradually added dropwise to a suspension of sodium hydride (60% in mineral oil, 378 mg, 9.4 mmol) in N,N-dimethylformamide (5 ml) in an argon atmosphere under ice cooling. The mixture was stirred at the same temperature for 2 hr. This solution was added dropwise to a solution of 2,5-dibromothiazole (1.0 g, 4.1 mmol) in tetrahydrofuran (13 ml) cooled to −20° C. (brine/ice water) through a cannula over a period of 20 min, and, while allowing the temperature to rise to around 0° C., the mixture was stirred for 2 hr. After the completion of the reaction, saturated brine was added thereto, and the mixture was extracted with ethyl acetate (20 ml×5). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate. The solvent was removed from the ethyl acetate washing liquor by distillation, and the residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:2). The resultant purification product was combined with the crystal prepared above to give ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (1.1 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:12])[N:10]=[N:11][C:6]=2[CH:5]=[C:4]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])[CH:3]=1.S(=O)(=O)(O)N.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](N)=[CH:29][CH:28]=1>>[CH3:19][C:14]1[C:13]([C:4]2[CH:3]=[C:2]([CH3:1])[C:7]3[N:8]=[C:9]([NH:12][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[N:10]=[N:11][C:6]=3[CH:5]=2)=[C:17]([CH3:18])[O:16][N:15]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1noc(C)c1-c1cc(C)c2nc(N)nnc2c1
Agent: NS(=O)(=O)O
Product: COc1ccc(Nc2nnc3cc(-c4c(C)noc4C)cc(C)c3n2)cc1
Temperature: 180 °C
Yield: 32.1 %

Procedure:
The mixture of 5-methyl-7-(3,5-dimethylisoxazol-4-yl)benzo[e][1,2,4]triazin-3-amine (compound 7 on scheme (CXXVIII)) (107 mg, 0.42 mmol), sulfamic acid (81.4 mg, 0.84 mmol), and 4-methoxybenzenamine 8 (774 mg, 6.3 mmol) was heated at 180° C. overnight. The product was purified by chromatography (SiO2/CH2Cl2) and the title product (48.7 mg, 32%) was obtained as a yellow solid. 1H NMR (CD2Cl2): δ 2.34 (s, 3H); 2.49 (s, 3H); 2.70 (s, 3H); 3.84 (s, 3H); 6.99 (d, J=8.9 Hz, 2H); 7.57 (s, 1H); 7.83 (d, J=8.9 Hz, 2H); 8.03 (s, 1H); 8.10 (br, 1H). MS (ESI+): m/z=362.1.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:32])=O>ClCCl>[CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([Cl:32])=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To 8.00 g of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 100 ml of dichloromethane 0.1 ml of DMF and 4 ml of oxalyl chloride were added. The reaction was stirred at rt for 16 h, then concentrated and co-distilled with toluene to obtain 8.47 g (100%) of the crude product as a brown solid, which was used without further purification.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1[NH:14][N:15]=[C:16]([C:18]([OH:20])=O)[CH:17]=1.[NH2:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:45][CH2:44][C:29]2[N:30]=[C:31]([NH:34][CH:35]3[CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:36]3)[N:32]=[CH:33][C:28]=2[CH2:27]1)=[O:25]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:43][CH:35]1[NH:34][C:31]1[N:32]=[CH:33][C:28]2[CH2:27][N:26]([C:24](=[O:25])[CH2:23][CH2:22][NH:21][C:18]([C:16]3[N:15]=[N:14][NH:13][CH:17]=3)=[O:20])[CH2:45][CH2:44][C:29]=2[N:30]=1
Reactant: NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: O=C(O)c1cn[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1)c1c[nH]nn1
Yield: 62.3 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.111 g; 1.5 equiv; 0.58 mmoles) to a solution of 2H-triazole-4-carboxylic acid (0.048 g; 1.1 equiv; 0.42 mmoles), 3-amino-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]propan-1-one (0.13 g; 1.0 equiv; 0.39 mmoles), and N,N-dimethyl-4-pyridinamine, (0.0094 g; 0.2 equiv; 0.077 mmoles) in dichloromethane (1.28 mL). Stir the reaction at ambient temperature for 16 hours. Load the mixture directly onto a silica gel column and purify by column chromatography (0 to 10% methanol in ethyl acetate) to afford N-{3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}-1H-1,2,3-triazole-4-carboxamide (0.105 g; 63%) as a white solid: MS (m/z): 433(M+1).
Reaction SMILES: [Br:1][C:2]1[C:7](=O)[C:6]([Br:9])=[CH:5][NH:4][CH:3]=1.P(Cl)(Cl)([Cl:12])=O.C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c(Br)c[nH]cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1c(Br)cncc1Br
Temperature: 100 °C

Procedure:
To 3,5-dibromo-4-(1H)-pyridone (W, 1.0 g, 3.97 mmol) was added phosphorous oxychloride (5 mL) and the mixture was heated at 100° C. for 2 h. The mixture was poured into ice/water (25 g) and basified by the addition of a saturated solution of sodium hydrogen carbonate. The mixture was extracted with dichloromethane (2×20 mL), the combined organic extracts were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+1): 271.8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:29][CH:28]([CH2:30][NH2:31])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][CH2:30][CH:28]3[CH2:29][O:26][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCC1COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(oxetan-3-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (d, 1 H), 7.89-7.87 (t, 1 H), 7.69-7.65 (m, 2 H), 7.50-7.46 (t, 1 H), 7.31 (d, 1 H), 7.24-7.21 (m, 1 H), 6.79-6.76 (t, 1 H), 6.04 (s, 1 H), 5.08 (s, 2 H), 4.74-4.70 (m, 2 H), 4.37 (t, 4 H), 3.61 (t, 4 H), 3.28 (m, 1 H), 2.35 (s, 3 H)
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][Cl:28])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([N:5]([CH2:4][C:3]([OH:29])=[O:2])[CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 59.7 g (0.135 mol) of {[4-(3-chloro-propoxy)-benzenesulfonyl]-(4-methoxybenzyl)-amino}-acetic acid methyl ester in 500 ml of MeOH, 500 ml of THF and 200 ml of H2O, 11.3 g of LiOH:H2O (0.27 mol) is added at 0–5° C. The mixture is allowed to warm to r.t. and stirred for 4 h. The reaction mixture is concentrated under reduced pressure and diluted with H2O and AcOEt. After acidifying with 2N HCl at 0–5° C., the mixture is extracted with AcOEt. The combined extracts are washed with brine and concentrated under reduced pressure to give {[4-(3-chloro-propoxy)-benzenesulfonyl]-(4-methoxy-benzyl)-amino]-acetic acid; NMR (CDCl3): 2.25–2.29 (m, 2H), 3.75 (t, 2H, J=6 Hz), 3.79 (s, 3H), 3.91 (s, 2H), 4.19 (t, 2H, J=6 Hz), 4.38 (s, 2H), 6.84 (d, 2H, J=8.56 Hz), 6.99 (d, 2H, J=8.56 Hz), 7.13 (d, 2H, J=9.04 Hz), 7.82 (d, 2H, J=9.04 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[NH:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.IC.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:18][C:17]1[CH:16]=[CH:15][N:14]([CH3:21])[C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(-c2noc(-c3[nH]ccc3Cl)n2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc(Cl)c1-c1nc(-c2ccc(Cl)cc2)no1
Temperature: 85 °C
Yield: 37.1 %

Procedure:
A mixture of 3-(4-chloro-phenyl)-5-(3-chloro-1H-pyrrol-2-yl)-[1,2,4]-oxadiazole (30.0 mg, 0.11 mmol), iodomethane (0.08 ml, 0.17 mmol) and potassium carbonate (23 mg, 0.17 mmol) in dimethylformamide (2 ml) was heated at 85° C. for 4 h. It was diluted by water (20 ml) and the mixture was extracted by EtOAc. The extracts were evaporated, and the residue was purified by column chromatography (EtOAc: Hexane=1:1) to give 12.0 mg (37%) of the title compound. 1H NMR (CDCl3): 8.11–8.07 (m, 2H), 7.50–7.45 (m, 2H), 6.84 (d, J=3.0 Hz, 1H), 6.28 (d, J=3.3 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([Br:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.C(OCC)C>[Br-:14].[C:28]1([P+:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: [Br-]
Product: c1ccc(C(c2ccccc2)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
6.2 parts of α-bromodiphenylmethane was dissolved in 100 parts of acetonitrile and 6.6 parts of triphenylphosphine was added thereto. The mixture was heated under reflux for 3 hr. The mixture was allowed to stand for cooling and then diluted with a small amount of diethyl ether. The resulting colorless crystals were collected by filtration and washed with a small amount of acetonitrile to obtain 10.5 parts of triphenyl (diphenylmethyl)phosphonium bromide (compound No. 66).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[C:20]2[C:21]([F:38])=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH:46]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]1>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[S:27]([NH:26][C:22]1[C:21]([F:38])=[C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:13][C:9]=2[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:51]([CH:46]3[CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:52])[N:8]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:29]
Reactant: NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Reactant: O=C(Cl)C1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1)C1CCCC1
Yield: 25.6 %

Procedure:
To a suspension of N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.1 g, 0.178 mmol) in dichloromethane (1.270 ml) was added triethylamine (0.062 ml, 0.444 mmol). A solution of cyclopentanecarbonyl chloride (0.024 g, 0.178 mmol) in dichloromethane (0.508 ml) was added dropwise and stirred. The reaction was quenched with water, extracted 2× with DCM, the organic extracts dried over MgSO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with DCM with MeOH (0% to 10%) and collected fractions to obtain the title compound as a solid (30 mg, 25% yield). MS (ESI): 659 [M+H]+.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][CH:13]=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Li].[Cl:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.O>C1COCC1.C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:13]([CH2:12][C:4]23[CH2:5][CH:6]4[CH2:7][CH:8]([CH2:9][C:2]([CH3:1])([CH2:11]4)[CH2:3]2)[CH2:10]3)[OH:14])[CH:26]=[CH:27][CH:28]=1
Reactant: CC12CC3CC(C1)CC(CC=O)(C3)C2
Reactant: Clc1cccc(Cn2ccnc2)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC12CC3CC(C1)CC(CC(O)C(c1cccc(Cl)c1)n1ccnc1)(C3)C2
Temperature: -60 °C
Reaction time: 1.75 h
Yield: 24.7 %

Procedure:
A solution of 4.05 g (20 mmol) of 2-(3-methyl-1-adamant-yl)-acetaldehyde (95% pure) in 40 ml of absolute THF was added, at about -60° C., to a solution of 20 mmol of lithium-N-(3-chlorobenzyl)-imidazole in THF/hexane, the said solution being prepared analogously to Example 105, and the mixture was stirred for 45 minutes at about -60° C. and for 1.75 hours at -60° C. to room temperature. After about 200 ml of water had been added, the mixture was extracted with ether. The residue (8.8 g) from the ether extract was crystallized from diisopropyl ether, and the product obtained was then recrystallized from acetonitrile. After isolation, 1.90 g (=24.7% of theory) of 2-(3-chlorophenyl)-2-(1-imidazolyl)-1-(3-methyladamant-1-ylmethyl)-ethanol of melting point 126° C. were obtained as a diastereomer which was pure according to thin layer chromatography. According to thin layer chromatography, the mother liquor contained further amounts of the same diastereomer, and the other diastereomer as the principal component.
Reaction SMILES: C(OP([O-])OCC)C.C(N(CC)CC)C.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([NH:35][C:36](=[O:38])[CH3:37])[CH:27]=[CH:28][C:29]=1[C:30](=[O:34])[CH:31](Br)[Br:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOC(C)=O>C1COCC1>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([NH:35][C:36](=[O:38])[CH3:37])[CH:27]=[CH:28][C:29]=1[C:30](=[O:34])[CH2:31][Br:32])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)Nc1ccc(C(=O)C(Br)Br)c(OCc2ccccc2)c1
Agent: CCOP([O-])OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)CBr)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 118.9 %

Procedure:
A solution of diethylphosphite (12.6 μL, 13.5 mg, 97.6 μmol) and triethylamine (13.6 μL, 9.9 mg, 97.6 μmol) in THF (0.1 mL) was added to a stirred solution of N-[3-benzyloxy-4-(2,2-dibromo-acetyl)-phenyl]-acetamide (41 mg, 92.9 μmol) in THF (1.5 mL) at room temperature, and the reaction stirred for 2 hours. The mixture was poured into EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give N-[3-benzyloxy-4-(2-bromo-acetyl)-phenyl]-acetamide (40 mg, >100%), which was seen by NMR to be contaminated with a diethylphosphite-derived contaminant. The material could be used successfully in the following steps without further purification. All analytical data was as reported above.