Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].[CH3:7][Si:8]([CH3:14])([CH3:13])[O:9][CH2:10][CH2:11]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:7][Si:8]([CH3:14])([CH3:13])[O:9][CH2:10][CH2:11][C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OCCBr
Reactant: c1cc[cH-]c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCC1=CC=CC1
Reaction time: 12 h
Yield: 64 %

Procedure:
150 ml of a 2.3 M sodium cyclopentadienylide solution in tetrahydrofurane (346 mmol) is slowly added to a solution of 68.2 g (346 mmol) 2-trimethylsiloxy-1-bromo-ethane in tetrahydrofurane. The immediate formation of a pinkish solid is observed. The reaction is maintained under stirring for 12 hours. Then, an ammonium chloride aqueous solution is added. The organic phase is extracted, dried with magnesium sulphate and the volatile part is distilled under vacuum, obtaining an orange oil. This oil is distilled in order to obtain a colorless oil. (Tb.: 63-65° C., 0.02 bar (15 mmHg.)). (40.3 g, 221 mmol. Yield:64%). 1H-NMR (CDCl3): 6.50-6.00 (m,3H), 3.75 (m,2H), 2.95 (m,2H), 2.65 (m,2H), 0.15 (s,9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>O>[NH2:12][CH2:13][CH2:14][NH:15][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCNc1ccc([N+](=O)[O-])c(N)n1

Procedure:
1 mmol of 2-amino-6-chloro-3-nitropyridine and 15 mmol of 1,2-diaminoethane were stirred at reflux for fourteen hours. The reaction mixture was concentrated in vacuo and solution of 1.5 mmol of NaOH in water was added. This solution was extracted twice with 95%/5% methylene chloride/methanol. The aqueous was then saturated with salt and extracted twice with 95%/5% acetonitrile/methanol and then finally extracted twice with 95%/5% ethylacetate/methanol. All organic fractions were combined and dried over sodium sulfate to obtain (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8]([Cl:12])(Cl)(Cl)=[O:9].Cl.CN(C)[C:16](=[O:18])[CH3:17]>>[O:7]([P:8]([Cl:12])([O:18][C:16]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:17]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)N(C)C
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Agent: Cl
Product: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Temperature: 70 °C

Procedure:
To a one liter four-inlet flask equipped with a temperature controller, a reflux condenser, a nitrogen feed and a mechanical stirrer, 2 moles (188 g) phenol and 500 ml N,N-dimethyl acetamide (DMAc) were added. The mixture was heated to 70° C. and then stirred. The mixture was heated to a temperature of 90° C. and the stirring was continued until phenol was dissolved completely. To this solution was added slowly 1.5 mole (230 g) phosphoryl chloride (POCl3) within two hours. The evolution of HCl gas was detected immediately. The temperature was increased to 135-138° C. and maintained at the reflux temperature for 12 hours after the addition of POCl3 was completed. HCl evolution subsided. The mixture was then cooled to room temperature and purified with dichloromethane to yield liquid diphenoxy phosphoryl chloride [DPOC; (II′)]. Yield, 96%. Anal. Calcd. for C12H10PO3Cl: C, 53.53; H, 3.72; O, 17.84; P, 11.52; Cl, 13.28. Found: C, 53.49; H, 3.70; O, 17.64; P, 11.64; Cl, 13.53. EIMS, m/z: 251 (90. M+).
Reaction SMILES: [CH2:1]([Si:3]1([CH2:19][CH3:20])[Si:6]([CH2:9][CH3:10])([CH2:7][CH3:8])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:4]1([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:2].[C:21]1([Si:27]([Li])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:41][Si:42]([CH3:45])([CH3:44])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[CH2:19]([Si:3]([CH2:1][CH3:2])([Si:6]([CH2:9][CH3:10])([CH2:7][CH3:8])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:4]([CH2:15][CH3:16])([CH2:17][CH3:18])[Si:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[Si:42]([CH3:45])([CH3:44])[CH3:41])[CH3:20]
Reactant: C[Si](C)(C)Cl
Reactant: CC[Si]1(CC)[Si](CC)(CC)[Si](CC)(CC)[Si]1(CC)CC
Reactant: [Li][Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[Si](CC)([Si](C)(C)C)[Si](CC)(CC)[Si](CC)(CC)[Si](CC)(CC)[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 52 mg (0.15 mmol) of octaethylcyclotetrasilane was added 0.75 ml (0.15 mmol) of a tetrahydrofuran solution (0.20M) of triphenylsilyllithium, and stirred at 0° C. for 15 minutes. Trimethylchlorosilane in an amount of 108 mg (1.0 mmol) was added, and reacted at room temperature for 3 hours. Hexane (2 ml) and saturated aqueous sodium bicarbonate solution (2 ml) were added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column chromatography (hexane) to give 42 mg (41% yield) of 2,2,3,3,4,4,5,5-octaethyl-1,1,1-trimethyl-6,6,6-triphenylhexasilane (4).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH:26]=[O:27])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[OH:27][CH:26](/[CH:25]=[CH:24]/[C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:29][CH:28]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])=[O:4]
Reactant: C#CC(=O)OCCOCCOC
Reactant: COc1ccc(C=CC=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCCOC(=O)C#CC(O)/C=C/c1ccc(OC)cc1
Reaction time: 0.08 h

Procedure:
A solution of 1.75 g (10.2 mmol) of 2-(2-methoxyethoxy)ethyl propiolate in 20 ml of tetrahydrofuran was treated at -78° under argon with 7 ml of n-butyllithium solution (1.6M in hexane). The mixture was stirred at -78° for 5 minutes and then a solution of 1.65 g (10.2 mmol) of 4-methoxycinnamaldehyde in 25 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was stirred at -78° for 5 minutes and then treated with 50 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed with water, dried over sodium sulphate, filtered and concentrated. Flash chromatography of the residue on 120 g of silica gel (elution agent methylene chloride/ether 4:1) yielded 2-(2-methoxyethoxy)ethyl (E)-4-hydroxy-6-(4-methoxyphenyl)-5-hexen-2-ynoate as a yellow oil.
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].Cl.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[N:48][CH:47]=1>N1C=CC=CC=1>[NH4+:48].[CH3:38][C:35]1[C:34]([O:39][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[N:48][CH:47]=2)=[C:33]([C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[CH:37][CH:36]=1)[C:40]([O-:42])=[O:41]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Product: CCC(C(=O)C(C)C(O)C(C)CCc1ccc(C)c(OC(=O)c2cccnc2)c1C(=O)[O-])C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Product: [NH4+]

Procedure:
A solution of the sodium salt of antibiotic X-537A (6.12 g.) in pyridine (10 ml.) was stirred at room temperature under nitrogen with 3 g. of nicotinoyl chloride hydrochloride for 13 days. Extraction and purification as in Example 22 gave a yellow residue which resisted crystallization. Attempted crystallization from hexane gave a gum which was dried on a clay plate to an amorphous solid, m.p. 81°-92° (dec.) [α]D25 -14.64° (C=1.04 in methanol).
Reaction SMILES: C([C:3]1([CH2:13][O:14][C:15]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([F:31])[CH:16]=2)[CH:10]2[CH2:11][CH:6]3[CH2:7]C(CC1C3)C2)#N.C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)CCCC1>>[CH:3]1([CH2:13][O:14][C:15]2[C:27]([CH:28]3[CH2:29][CH2:30]3)=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:31])[CH:16]=2)[CH2:10][CH2:11][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCCC2)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 6 and making non-critical variations to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was obtained as a colorless solid (3.0 g, 46%): 1H NMR (300 MHz, CDCl3) δ 7.27 (d, J=7.72 Hz, 1H), 6.85 (d, J=7.72 Hz, 1H), 3.92 (d, J=6.78 Hz, 2H), 2.38-2.22 (m, 1H), 2.05-1.89 (m, 1H), 1.83-1.67 (m, 2H), 1.64-1.44 (m, 4H), 1.41-1.26 (m, 2H), 0.89-0.79 (m, 2H), 0.60-0.52 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.[F:9][C:10]([F:15])([F:14])[C@@H:11]1[CH2:13][O:12]1>C(#N)C>[O:7]=[S:4]1(=[O:8])[CH2:5][CH2:6][N:1]([CH2:13][C@H:11]([OH:12])[C:10]([F:15])([F:14])[F:9])[CH2:2][CH2:3]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: O=S1(=O)CCNCC1
Solvent: CC#N
Product: O=S1(=O)CCN(C[C@H](O)C(F)(F)F)CC1
Yield: 32.8 %

Procedure:
In a 2 ml vial, thiomorpholine 1,1-dioxide (200 mg, 1.48 mmol) was combined with acetonitrile (5.33 ml) to give a colorless solution. (S)-2-(trifluoromethyl)oxirane (332 mg, 257 μl, 2.96 mmol) was added and the resultant mixture was stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuo to afford 120 mg of (S)-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-1,1,1-trifluoro-propan-2-ol as an oil, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:15]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methoxybenzylamine (23 g) was dissolved in 150 ml of tetrahydrofuran, and a solution of 32 g of t-butyl dicarbonate in tetrahydrofuran (50 ml) was added thereto. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and successively washed with 1N hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give t-butyl N-(3-methoxybenzyl)carbamate. The resulting t-butyl N-(3-methoxybenzyl)carbamate was then dissolved in 250 ml of acetonitrile, 30 g of N-bromosuccinimide was added thereto under ice-cooling, the mixture was stirred at room temperature for 3 hours, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water and then with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by a silica gel column, to give 36 g of the title compound in the 2:1 hexane-diethyl ether fraction.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(Cl)(Cl)=O.N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10 g of 2,6-dimethylbenzoic acid in 22 g thionyl chloride was stirred at reflux temperature for 2 hours. Removal of the excess thionyl chloride afforded the crude acid chloride as a yellow oil. This intermediate was added to a stirred solution of 4 mL of methanol in 10.8 mL pyridine at 65°-70° C. After completion of the addition, the resulting mixture was stirred at room temperature for 2 hours and then poured into 75 mL ice-water. The aqueous layer was extracted with four 50-mL portions of ether and the combined organic extracts were backwashed with saturated sodium bicarbonate solution, 5% aqueous hydrochloric acid, and water. Drying and evaporation of the solvent gave a pale yellow oil which was purified by bulb-to-bulb distillation (40°-50° C., 0.5 mm Hg) to afford 9.5 g of pure 2,6-dimethylbenzoic acid, methyl ester as a colorless liquid; IR (film) 1725 cm-1 ; NMR(CDCl3) δ 2.3 (s, 6H), 3.9 (s, 3H), 7.0-7.4 (m, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[C:26]([OH:28])=[O:27].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>O1CCCC1>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: BrCCCCCCBr
Reactant: Cc1ccccc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(O)c1ccccc1CCCCCCCBr
Temperature: 0 °C

Procedure:
Diisopropylamine (61.8 ml, 441 mmoles) was dissolved in tetrahydrofuran (200 ml) and cooled to 0° C. in an ice-methanol bath while stirring under argon. A 2.6 M solution of n-butyllithium in hexane (170 ml, 441 mmoles) was added dropwise. Toluic acid (30.0 g, 221 mmoles) was then added and the reaction immediately turned a deep red color. This mixture was added slowly to a solution of 1,6-dibromohexane (84 ml, 551 mmoles) in tetrahydrofuran (200 ml) at 0° C. Following the addition, the ice bath was removed and the reaction mixture was stirred at room temperature under argon for 18 hours. The solvent was evaporated and the residue dissolved in ether. The ether was extracted with cold 1 N sodium hydroxide solution. The pH of the aqueous phase was adjusted to 8.0 with cold concentrated hydrochloric acid and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate, filtered and evaporated to afford the desired product.
Reaction SMILES: C([Li])CCC.[CH:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=O.[Cl-].[NH4+].[C:16](OCC)(=[O:18])C.[CH2:22]1[CH2:26][O:25]C[CH2:23]1>>[CH2:10]([O:11][C:12]1[CH:23]=[C:22]([CH:26]=[O:25])[CH:6]=[N:8][C:13]=1[O:18][CH3:16])[CH3:9]
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CCOc1cc(C=O)cnc1OC
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the 5.28 g of light yellow oil in 80 ml of THF there was added dropwise 9.07 ml of n-butyllithium (2.64 M, hexane solution) at −78° C. over a period of 20 minutes. After stirring at −78° C. for 3 hours, 4.59 ml of N-formylmorpholine was added. After further stirring at −78° C. for 20 minutes, the temperature was slowly allowed to rise to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give 5-ethoxy-6-methoxypyridine-3-carbaldehyde (2.23 g) as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]2([OH:25])[C:17]3[C:12](=[CH:13][CH:14]=[C:15](C)[CH:16]=3)[N:11]([CH2:19][CH2:20]C(C)C)[C:10]2=[O:24])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:26]C1C=C2C(=CC=1)N(CC)C(=O)C2=O.CC1C=CC=CN=1>>[Cl:26][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:19][CH3:20])[C:10](=[O:24])[C:9]2([OH:25])[CH2:8][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Reactant: CCN1C(=O)C(=O)c2cc(Cl)ccc21
Solvent: Cc1ccccn1
Product: CCN1C(=O)C(O)(Cc2ccccn2)c2cc(Cl)ccc21

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-chloro-1-ethylindoline-2,3-dione and 2-methylpyridine (purchased from Fisher Scientific). 1H-NMR δ 8.60 (d, 1H), 7.65 (dd, 1H), 7.27 (m, 3H), 7.09 (d, 1H), 6.75 (m, 2H), 3.72 (m, 2H), 3.35 (d, 1H), 3.09 (d, 1H), 1.21 (t, 3H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[I:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>C1COCC1.C(Cl)Cl>[I:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (12.1 g, 62.9 mmol), 1-hydroxybenzotriazole hydrate (9.63 g, 62.9 mmol), and morpholine (9.13 g, 105 mmol) was added to a solution of 4-iodobenzoic acid (13 g, 52.4 mmol) in a mixture of THF (250 mL) and methylene chloride (50 mL). After stirred at 25° C. for 20 hr, the solvent was removed and flash silica gel chromatography (step gradient elution with methylene chloride containing 0 to 3% MeOH) afforded (4-iodophenyl)(morpholino)-methanone (15.1 g). MS (ESI) m/z 317.9 (M+H). 1H NMR (CDCl3) δ ppm 7.76 (2H, d, J=8.24 Hz), 7.14 (2H, d, J=8.24 Hz), 3.23-4.00 (8H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.COCCOC.CO.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)SC)=[O:21]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:23]([NH:22][C:20](=[O:21])[O:19][CH3:18])[NH:9][C:4]=2[CH:3]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(Br)cc1N
Solvent: CCOCC
Solvent: COCCOC
Solvent: CO
Product: COC(=O)Nc1nc2ccc(Br)cc2[nH]1
Temperature: 105 °C
Yield: 77.4 %

Procedure:
To a slurry of 4-bromobenzene-1,2-diamine (2.1 g, 11 mmol), 1,2-dimethoxyethane (20 mL) and methanol (5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (4.0 g, 19 mmol). The reaction mixture was heated (105° C.) for 12 h and then diluted with ethyl ether (100 mL). The resulting precipitate was collected by filtration and rinsed with ethyl ether (2×25 mL) to provide methyl 6-bromo-1H-benzo[d]imidazol-2-ylcarbamate (2.3 g, 77% yield). MS (EI) for C9H8BrN3O2: 271 (MH+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:40][N:41]([CH3:47])[CH:42]1[CH2:46][CH2:45][NH:44][CH2:43]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:44]1[CH2:45][CH2:46][CH:42]([N:41]([CH3:47])[CH3:40])[CH2:43]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CN(C)C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N(C)C)C3)ccc2[nH]1
Yield: 68 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3-(dimethylamino)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (68%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[CH3:18][N:19]([CH3:32])[S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21]>>[OH:13][S:12]([NH:11][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:25]3[CH:24]=[C:23]([S:20]([N:19]([CH3:32])[CH3:18])(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=3)[CH:3]=2)[CH2:7]1)([OH:14])[CH:15]([CH3:17])[CH3:16]
Reactant: CN(C)S(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Product: CC(C)S(O)(O)NC1Cc2ccc(-c3cccc(S(=O)(=O)N(C)C)c3)cc2C1

Procedure:
The title compound was prepared from N-(5-iodo-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide and {3-[(dimethylamino)sulfonyl]phenyl}boronic acid (WO2003004472) in a similar manner to Example 1.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=O)[CH2:6][C:5](=[O:10])[CH2:4]1)[CH3:2].C([O-])(=O)C.[NH4+:15]>>[NH2:15][C:7]1[CH2:8][CH:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:10])[CH:6]=1
Reactant: [NH4+]
Reactant: CCC1CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Product: CCC1CC(=O)C=C(N)C1

Procedure:
In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-ethylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[CH2:3][CH2:4][CH:5]([C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)=[CH:11][CH:12]=1.O1CCCC1.[OH-].[Li+]>CO>[F:39][C:2]([F:1])([F:38])[CH2:3][CH2:4][CH:5]([C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:23]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[N:14]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of crude (+/−)-ethyl N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alaninate (52 mg, 0.093 mmol) was dissolved in methanol (0.20 ml) and tetrahydrofuran (0.10 ml) and treated with aqueous lithium hydroxide (0.093 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient temperature for 1 hour. The crude reaction mixture was concentrated in vacuo and the residual solid was dissolved in water (0.50 ml) and treated with aqueous 1.0M hydrochloric acid until approximately pH 6 was reached, resulting in the precipitation of racemic N-{4-[4,4,4-trifluoro-1-({6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}amino)butyl]benzoyl}-beta-alanine as a white gummy solid. The two enantiomeric products were separated by chiral SFC Column: Chiralpak AD-H. Dimensions: 21×250 mm. Mobile Phase: 70/30 CO2/methanol, (peak 1, 0.30 g, 22% and peak 2, 0.30 g, 22%). Flow Rate: 65 mL/min. Modifier: none. Analytical SFC: Chiralpak AD-H, 4.6 mm×25 cm: SFC Mobile Phase 70:30 CO2/Methanol, 2.5 mL/min, analytical retention time: 2.97 min (Isomer 1) and 5.15 (Isomer 2). 1H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 7.73-7.84 (m, 4H), 7.70 (d, J=8.8 Hz, 1H), 7.37-7.43 (m, 2H), 6.98 (br. dd, J=8.6, 2.0 Hz, 1H), 6.73-6.86 (m, 1H), 4.48 (br. t, J=6.3 Hz, 1H), 3.73 (br. q, J=5.9 Hz, 2H), 2.72 (br. t, J=5.8 Hz, 2H), 2.06-2.34 (m, 4H). MS (M+1): 530.3.