Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH3:20])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39](Cl)([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]=1[O:50][CH3:51])([CH3:29])([CH3:28])[CH3:27].O>CCOCC.C([Cu])#N>[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39]([CH:16]2[C:15]3[C:19](=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=4)[CH:12]=[CH:13][CH:14]=3)[CH:18]=[C:17]2[CH3:20])([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:31]=1[O:50][CH3:51])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC1=Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 11.5 g (43.8 mmol) of 7-(4-tert-butylphenyl)-2-methyl-1H-indene in 300 ml of ether, 17.0 ml (42.5 mmol) of 2.5 M nBuLi in hexanes was added in one portion at −78° C. This mixture was stirred overnight at room temperature, then cooled to −60° C., and 150 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −70° C., and 16.2 g of (6-tert-butyl-5-methoxy-2-methyl-4-phenyl-1H-inden-1-yl)(chloro)-dimethylsilane (42.08 mmol) in 150 ml of ether was added. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water was added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was additionally washed by dichloromethane. The combined organic elute was evaporated to dryness, and the obtained yellowish oil was purified by flash chromatography on silica gel 60 (40-63 um; eluent: hexane-dichloromethane, from 10:1 to 3:1, vol.). This procedure gave 23.4 g (91%) of the title compound as yellowish glass.
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31]OS(C)(=O)=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:37][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][S:20][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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
Reactant: CS(=O)(=O)OCCOCCOCCOCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: FCCOCCOCCOCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 71 %

Procedure:
A stirring solution of methanesulfonic acid 2-{2-[2-(2-tritylsulfanyl-ethoxy)-ethoxy]-ethoxy}-ethyl ester (71.67 mg, 0.14 mmol) and tetrabutylammonium fluoride (1.1 M in THF, 127 μl, 0.14 mmol) was heated at 90° C. for 30 minutes. The mixture was cooled to ambient temperature and evaporated to dryness. Purification of product was by flash chromatography using ethyl acetate/hexane, (1:1) to give the product (71%) as a colourless oil.
Reaction SMILES: O.[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[K+:7].[K+].[K+].[Ca:10].P([O-])([O-])([O-])=[O:12].[C:16]([OH:19])(=[O:18])[CH3:17]>>[OH2:3].[C:16]([O-:19])(=[O:18])[CH3:17].[Ca+2:10].[C:16]([O-:19])(=[O:18])[CH3:17].[OH2:12].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[K+:7].[K+:7].[K+:7]
Reactant: CC(=O)O
Reactant: [Ca]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)[O-]
Product: [Ca+2]

Procedure:
Calcium acetate hydrate and potassium orthophosphate hydrate solutions were prepared as described in Example 1. The potassium orthophosphate hydrate solution was divided in half and acetic acid was added to one of the two portions until the pH of the solution was 7.4 (volume depends on total solution volume, for example 500 mL solution needs about 23 mL of glacial acetic acid). Proportional amounts of each of the three solutions were then measured out to create a calcium to phosphate ratio of 1.67 and pH of 7.4 (final concentrations of ions if they were to remain in solution would be 0.5 m/0.3 m). A 20 mL reaction required 10 mL of the calcium solution to be measured and poured into a beaker and 8.5 mL of the phosphate solution (unadjusted) to be added to the calcium solution followed by 1.5 mL of the pH adjusted solution. Agitation via stirring with a glass rod was then performed until the solution appeared completely mixed and white (a gelation is not seen). The slurry was not aged. The concentrate or solution was then dried in an oven at 70° C. for 24 hours and desiccated until use or immediately atomized onto a TEM grid for characterization.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[CH:9][S:10][CH:11]=1.IC>O1CCCC1>[CH3:1][C:9]1[S:10][CH:11]=[C:7]([CH3:6])[C:8]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1cscc1C(=O)O
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1csc(C)c1C(=O)O
Temperature: -78 °C
Yield: 82.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 18.6 mL, 46 mmol) was added to a pre-cooled solution of 4-methylthiophene-3-carboxylic acid (3.0 g, 21 mmol) in dry tetrahydrofuran (THF, 35 mL) at −62° C. The reaction mixture was stirred at −78° C. for an hour, allowed to warm to −40° C. and re-cooled to −78° C. before adding iodomethane (3.28 mL, 7.49 g, 53 mmol). After addition, the reactants were stirred at −78° C. for an hour and then allowed to warm to room temperature over 14 hours and quenched with water (20 mL). The organic phase was extracted with dilute sodium hydroxide (0.2 N, 3×30 mL). The combined aqueous extracts were washed with ether (2×30 mL), cooled in an ice bath and acidified to pH 3 using concentrated hydrochloric acid. The resultant precipitate was extracted with ether (3×50 mL). The combined ethereal extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate, concentrated under reduced pressure and recrystallised from ethyl acetate/hexane to give product as an amorphous white solid (2.7 g, 82%): mp 164-165° C.; 1H NMR (CDCl3) δ 6.65 (q, 1H), 2.73 (s, 3H), 2.43 (d, 3H); EI/MS 156 m/e (M+); IR (liq film) 1664 cm−1; Calcd for C7H8O2S: C, 53.8; H, 5.16; Found: C, 53.8; H, 5.11.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[N:26]1[CH2:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1C(=O)CCC1>[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[N:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[C:27]1=[O:32]
Reactant: O=C1NCCCN1C1Cc2ccccc2C1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1N(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CCCN1C1Cc2ccccc2C1
Yield: 14.7 %

Procedure:
Synthesized according to general procedure 43. The reaction was set up with 4-iodo-N-(thiazol-2-yl)benzenesulfonamide (250 mg, 0.68 mmol), 1-(2,3-dihydro-1H-inden-2-yl)tetrahydropyrimidin-2(1H)-one (138 mg, 0.68 mmol), copper(I) iodide (267 mg, 1.4 mmol), potassium carbonate (282 mg, 2.0 mmol), and NMP (1.7 mL). The dark mixture was purified via silica gel chromatography using 10% MeOH in CH2Cl2 to obtain the desired urea as a white solid (45 mg, 0.10 mmol, 15% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 7.71 (dd, J=1.9, 6.9 Hz, 2H), 7.45 (dd, J=1.9, 6.9 Hz, 2H), 7.26-7.21 (m, 3H), 7.23-7.11 (m, 2H), 6.83 (d, J=4.5 Hz, 1H), 5.25-5.19 (m, 1H), 3.68-3.65 (m, 2H), 3.20 (t, J=5.9 Hz, 2H), 3.09-2.98 (m, 4H), 2.01-1.91 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=455.3; tR=2.98 min.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[NH:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: C1CCNC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N6CCCC6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 2.8 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (56 mg, 0.082 mmol) in THF (2 mL) was added polystyrene carbodiimide (0.15 mg, 0.17 mmol) and 1-hydroxybenzotriazole hydrate (22 mg, 0.16 mmol), and then the reaction mixture was stirred at room temperature under nitrogen. After 15 min, pyrrolidine (11 mg, 0.16 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen. After 5 h, the reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic). The resulting product was lyophilized from acetonitrile (3 mL) and water (1 mL) to give (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(pyrrolidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone (1.7 mg, 2.8%) as a mixture of diastereomers and as a dark red solid: 1H NMR (500 MHz, CD3OD) δ 8.10 (s, 1H), 6.64 (s, 1H), 6.17 (s, 0.3H), 6.01 (s, 0.7H), 4.96-4.87 (m, 2H), 3.74 (s, 3H), 3.64 (s, 1H), 3.57 (s, 3H), 3.52 (d, J=18.0 Hz, 3H), 3.46-3.39 (m, 6H), 3.26-3.20 (m, 1H), 3.08-3.02 (m, 2H), 2.08 (s, 3H), 1.93-1.87 (m, 4H), 1.28 (d, J=6.0 Hz, 2.1H), 1.22 (d, J=6.0 Hz, 0.9H); MS (ESI+) m/z 737 (M+H); HPLC 94.4% (AUC), tR 10.71 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:27]=[CH2:28])=[C:4]([CH:8]=[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=O.Cl.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.O.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]([CH:27]=[CH2:28])=[C:4]([CH:8]=[C:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:20][CH:21]=2)[C:10]=1[C:11]([F:14])([F:12])[F:13])[C:5]([NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37])=[O:7]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Reaction time: 16 h
Yield: 113 %

Procedure:
To a solution of 3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoic acid (0.05 g), trans-2-aminocyclohexanol hydrochloride (0.03 g), 1-hydroxybenzotriazole (0.03 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.04 g) in dichloromethane (5.00 mL) was added triethylamine (0.04 g), and the mixture was stirred for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.07 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[C:8]1(=[O:12])[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)CBr
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(c1)CCCC2=O
Reaction time: 18 h

Procedure:
To a solution of 6-hydroxy-1-tetralone (2.62 g) in acetone (50 ml) was added anhydrous potassium carbonate (2.23 g) followed by methyl bromoacetate (1.52 ml) and the resulting mixture was stirred for 18 hours. The mixture was filtered and the solvent was evaporated to give a yellow solid. Recrystallisation from ethyl acetate gave methyl tetralone-6-oxyacetate (2.28 g): NMR (d6DMSO) 6 1.95-2.05(m,2H), 2.45-2.55(m,2H), 2.9(t,2H), 3.7(s,3H), 4.9(s,2H), 6.85-6.9(m,2H), 7.8(d,1H); m/e 235(M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:34])[CH2:18][O:19][CH2:20][C:21]([NH:23][C:24]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])[CH:13]=[CH:14][CH:15]=1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:24]([NH:23][C:21](=[O:22])[CH2:20][O:19][CH2:18][C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:11]=2)=[O:34])=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27]
Reactant: OB(O)c1ccsc1
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccsc2)c1

Procedure:
Using the same method as in Example 19-(ii), 3-thiopheneboronic acid was reacted with the 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 19-(i) to give 5-chloro-2-([(2-([3-(thiophene-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 82%).
Reaction SMILES: [K+].[CH3:2][N:3]([CH3:20])[C:4]1[CH:19]=[CH:18][C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([O-])=[O:16])=[CH:11][C:9]=3[S:10][C:6]=2[CH:5]=1.C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1>[CH3:2][N:3]([CH3:20])[C:4]1[CH:19]=[CH:18][C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([Cl:24])=[O:16])=[CH:11][C:9]=3[S:10][C:6]=2[CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)c1ccc2c(c1)sc1cc(C(=O)[O-])ccc12
Agent: [K+]
Solvent: c1ccccc1
Product: CN(C)c1ccc2c(c1)sc1cc(C(=O)Cl)ccc12

Procedure:
To a suspension of 1.9 g. of 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. of refluxing benzene was added over a period of 20 minutes a solution of 1.2 g. of oxalyl chloride in 25 ml. of benzene. The solution was then stirred and refluxed for 3 hours. The hot solution was filtered, and the filtrate was distilled to dryness in vacuo (steam bath, rotary evaporator). The residue of crude 7-dimethylaminodibenzothiophene-3-carbonyl chloride weighed 1.8 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].[CH:19](=O)[CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C(Cl)Cl>[C:10]([C:9]1[C:4]([CH2:3][NH:2][CH2:19][CH2:20][CH2:21][CH3:22])=[C:5]([OH:18])[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CCCC=O
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 0.47 g (2.0 mmol) of the product of Example 19 and 0.15 g (2.1 mmol) of n-butyraldehyde in 10 mL of 1,2-dichloroethane was added 25 drops of acetic acid and 3 g of finely powdered 4 Å molecular sieves. The mixture was stirred 5 h at room temperature at which point 1 g of sodium triacetoxyborohydride was added. The reaction mixture was stirred overnight at room temperature, then diluted with 10 mL CH2Cl2 and filtered through a layer of Celite filter aid. The filtrate was washed with excess saturated aq. NaHCO3, the aqueous layer was extracted with CH2Cl2, then the organic layers were combined, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0-10% EtOAc in CH2Cl2. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][O:6][C:5]=1[CH2:9][N:10]([CH3:12])[CH3:11].Cl.C=O.[C:16](=O)([O-])[O-:17].[Na+].[Na+]>C(O)(=O)C>[CH3:12][N:10]([CH2:9][C:5]1[O:6][C:7]([CH2:16][OH:17])=[CH:8][C:4]=1[CH2:3][O:2][CH3:1])[CH3:11]
Reactant: COCc1ccoc1CN(C)C
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COCc1cc(CO)oc1CN(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-methoxymethyl-N,N-dimethyl-2-furanmethanamine (7 g), acetic acid (60 ml), concentrated hydrochloric acid (30 ml) and paraformaldehyde (3.7 g) was stirred at ambient temperature for 5 hours. The mixture was basified with sodium carbonate, and extracted with diethyl ether (200 ml). The ethereal extract was dried over anhydrous sodium sulphate and the solvent evaporated in vacuo. The residue was distilled affording the title compound (3.5 g) as an off-white waxy solid, b.p. 90°/5×10-2 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.ClS([N:20]=[C:21]=[O:22])(=O)=O>C(#N)C>[C:21]([C:4]1[C:3]2[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:22])[NH2:20]
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of 2.0 g (9.9 mmol) of methyl 4,7-dimethylindole-2-carboxylate in 200 ml of anhydrous acetonitrile was cooled to 0° C. A solution of 3 ml (9.9 mmol) of chlorosulfonylisocyanate in 50 ml of anhydrous acetonitrile was added dropwise over a period of 15 minutes and the reaction mixture was stirred at room temperature for 30 minutes. After distilling off acetonitrile under reduced pressure, the residue was dissolved in 15 ml of acetonitrile-water (4:1). The pH of the solution was adjusted to 8 by gradually adding 10% potassium hydroxide aqueous solution dropwise. The white crystals precipitated were separated by filtration and air-dried and then dried under reduced pressure to provide 1.0 g of white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(=O)=O.[CH:15]([OH:18])(C)[CH3:16].ClOC(C)(C)C.CC[C:27](OCC)=[S:28]>C(Cl)Cl.C(N(CC)CC)C>[CH3:27][S:28][CH:16]1[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=2)[NH:1][C:15]1=[O:18]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=S)CC
Reactant: CC(C)O
Agent: CC(C)(C)OCl
Agent: O=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Temperature: 15 °C
Reaction time: 0.08 h

Procedure:
To a solution of 30.8 of p-aminobenzotrifluoride predissolved in 450 ml. of methylene chloride, cooled to -58°C. (dry ice/isopropanol bath), and under an atmosphere of nitrogen, is added dropwise a solution of 21.1 ml. of t-butyl hypochlorite in 30 ml. of methylene chloride over 30 minutes while the reaction miture is maintained at -55° to 58°C. After the reaction mixture is stirred an additional five minutes, a solution of 25.6 g. of ethyl methylthioacetate in 30 ml. of methylene chloride is added dropwise over a period of 20 minutes while the reaction mixture is maintained at -55° to -58°C. The reaction mixture is stirred one hour at -55° to -65°C. and 60 ml. of methylene chloride is added to facilitate stirring. A solution of 25 ml. of triethylamine in 25 ml. of methylene chloride is added dropwise over a period of 10 minutes while the reaction mixture is maintained at -50°C. to -60°C. After an additional three minutes stirring, the cold bath is removed and the reaction mixture allowed to warm to 15°C. over a period of two hours; then 100 ml. of water is added. The organic phase is separated and concentrated in vacuo to an oil which is then dissolved in 100 ml. of ether. The ethereal solution is treated with 50 ml. of 2N hydrochloric acid, and the mixture is stirred overnight at room temperature. The phases are separated and the product is obtained in two portions by crystallization with cooling, followed by concentration of the mother liquors to a solid in vacuo. Recrystallization from ether/pentane gives 3-methylthio-5 -trifluoromethyl-2-indolinone, m.p. 136°-138°C.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([C:24]([OH:26])=O)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([C:24]([Cl:3])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(-c2cccnc2C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(-c2cccnc2C(=O)Cl)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (8 mL) and N,N-dimethylformamide (few drops) are added to a solution of 3-(3-methoxy-phenyl)-pyridine-2-carboxylic acid (11.86 g) in dichloromethane (80 mL). The mixture is heated to 40° C. and stirred at this temperature overnight. The solution is then concentrated and the residue is taken up in toluene and concentrated again to give the crude title compound that is used without further purification in the next step. Yield: 12.80 g (crude).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH:5](O)[CH2:6][N:7]=[N+:8]=[N-:9])[CH3:2].C(N(S(F)(F)[F:20])CC)C>C1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH:5]([F:20])[CH2:6][N:7]=[N+:8]=[N-:9])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(OCC)C(O)CN=[N+]=[N-]
Solvent: c1ccccc1
Product: CCOC(OCC)C(F)CN=[N+]=[N-]
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirring solution of 3-azido-2-hydroxypropanal diethyl acetal (7.32 g, 38.73 mmol) in dry benzene (50 mL) was added diethylaminosulfurtrifluoride (DAST; 20.6 mL) at -78° C. After the addition, the solution was stirred at room temperature for an hour, then heated to 70° C. for 12 hours. The reaction was quenched by the addition of methanol at zero degrees C. and dilution with water. After dichloromethane extraction, the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified with silica gel column chromatography (hexane: ether=9:1, volume/volume) to yield 3-azido-2-fluoropropanal diethyl acetal as an oil (65 percent); Rf =0.84 EtOAc:hexane=2:3) 1H-NMR (CD3Cl) δ 1.215~1.219 (6H, m) 3.526 (2H, dm, J=15.3 Hz), 3.642~3.670 (2H, m), 3.680~3.808 (2H, m), 4.514 (1H, dm, J=45.9 Hz) ppm.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][CH:14]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Step A To a solution of N-Boc-1,4-phenylene diamine (Aldrich, 1.00 g, 4.82 mmol) in CH2Cl2 (12 ml) were added N,N-diisopropylethylamine (1.26 g, 9.76 mmol) and ethyl bromoacetate (Aldrich, 813 mg, 4.87 mmol). The mixture was allowed to stir at rt overnight and then taken up in EtOAc (300 ml) and washed with sat. aqueous Na2CO3, water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give ethyl 2-(4-(tert-butoxycarbonylamino)phenylamino)acetate as a light brown oil (1.33 g, 94%).