Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][C:39]=1[O:53][CH3:54])=[O:36])[N:29]2[CH3:34]>>[CH3:21][N:20]([CH3:22])[C:18](=[O:19])[CH2:17][N:14]1[CH2:15][CH2:16][C@@H:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([NH:37][C:35]([C:28]4[N:29]([CH3:34])[C:30]5[C:26]([CH:27]=4)=[C:25]([O:24][CH3:23])[CH:33]=[CH:32][CH:31]=5)=[O:36])=[C:39]([O:53][CH3:54])[CH:40]=3)[N:3]=2)[CH2:13]1
Reactant: Cc1nccn2c([C@@H]3CCN(CC(=O)N(C)C)C3)nc(Br)c12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Product: COc1cc(-c2nc([C@@H]3CCN(CC(=O)N(C)C)C3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Yield: 91.1 %

Procedure:
Reaction of (R)-2-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-N,N-dimethylacetamide (22 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (23 mg) according to the procedure described in example 4 step 4c and purification using prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid) gave (R)—N-(4-(3-(1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-3-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (28.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:31]=[CH:30][C:17]4[O:18][CH2:19][C:20]5[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[F:32].[SH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[C:36]([CH2:35][CH2:34][S:33][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]#[N:29])[C:20]=2[CH2:19][O:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:32])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:38])=[O:37]
Reactant: N#Cc1cccc2c1COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2O
Reactant: O=C(O)CCS
Product: N#Cc1cccc2c1COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
2-(7-Chloro-6-fluoroquinolin-2-yl)methoxy-7-cyano-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[I:21]N1C(=O)CCC1=O>CC(C)=O>[I:21][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:13]=[CH:14][CH:15]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(I)c3c2)c1
Yield: 48.4 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 1, N-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (800 mg, 3 mmol) was iodinated with N-iodo succinimide (764 mg, 3 mmol) in acetone (5 ml) to afford 600 mg (50% yield) of the pure product. LCMS: m/z=413.4 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1F)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-fluorophenyl isocyanate (0.139 ml, 1.22 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 146 mg (46.9%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[C:1]([O:8][CH3:9])=[O:7]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of dimethyl malonate (5.53 g) in THF (100 mL) was added 60% sodium hydride (1.84 g) under ice-cooling, and the mixture was stirred for 30 min. 4-Nitrobenzyl bromide (9.04 g) was added to this mixture under ice-cooling, and the mixture was allowed to warm to room temperature while stirring for 4 hr. The reaction mixture was adjusted to pH=2-3 by the addition of dilute hydrochloric acid, the precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine and concentrated under reduced pressure to give the title compound (7.66 g) as a pale-yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].CN(C=O)C.[N-:18]=[N+:19]=[N-:20].[Na+]>CCOC(C)=O>[N:18]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:19]=[N-:20]
Reactant: CSc1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A solution consisting of 2-bromo-1-(4-methylsulfanyl-phenyl)-ethanone (2.00 g, 8.16 mmol) and DMF (7 mL) was cooled to 15° C. and treated portion-wise with sodium azide (583 mg, 8.98 mmol). Once addition was complete, the reaction mixture was stirred for 3 h with gradual warming to rt. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (25 mL×2), NaHCO3 (satd., 25 mL×2), and brine. The combined organic phases were dried (Na2SO4) and concentrated to dryness to yield the title compound (1.69 g, 100%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[C:6]([CH:9]=3)[CH:7]=[O:8])=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: O=Cc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 5-iodo-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.50 g, 4.35 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (214 mg, 5.00 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:27][N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.ClCCl>>[CH2:1]([O:8][C:9]1[C:10]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCNCC3)c(OCc3ccccc3)ccc21
Yield: 41.2 %

Procedure:
tert-Butyl 4-{[5-(benzyloxy)-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}piperazine-1-carboxylate (30 mg, 0.05 mmol, Intermediate 63) was stirred with a 50/50 mixture of TFA/dichlorometane (3 mL) in room temperature for four hours. The solvent was removed at reduced pressure and the crude was purified on a preparative HPLC, method B, to give 9.5 mg (40%) of a colorless oil. MS (ESI+) for C26H27N3O3S m/z 462 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].[P:38]([O:45]CC)([O:42]CC)[O:39]CC>>[P:38]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])([OH:45])([OH:42])=[O:39]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Reactant: CCOP(OCC)OCC
Product: O=P(O)(O)CCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
A mixture of 5.23 g of 1-bromo-11-(heptadecafluorooctyl)undecane and 4.2 g of triethyl phosphite was heated at 150° C. After 18 hr, diethyl ethylphosphonate and other volatiles were distilled from the reaction mixture, b.p. 30-50° C. at 0.05 torr (7 Pa). The concentrate was combined with an additional 2.0 g of triethyl phosphite, and the mixture was heated at 150° C. After 3 hr, volatiles were again distilled, and the crude 1-diethylphosphono-11-(heptadecafluorooctyl)undecane was dissolved in 10 mL of dichloromethane. To this solution was added 3.1 g of bromotrimethylsilane. After 18 hr at room temperature, the solution was concentrated to a nearly colorless liquid, and the intermediate silylphosphonate ester was dissolved in 200 mL of methanol. The resultant solution was stirred at room temperature for 3 hr and cooled to 0° C. The crude product was collected by filtration, and recrystallization from methanol afforded 2.32 g of 1-phosphono-11-(heptadecafluorooctyl)undecane (CF3(CF2)7 (CH2)11PO3H2) as white crystals, m.p. 115-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[C:7](OC(C)(C)C)=[O:8].[BH4-].[Li+]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][CH:6]([CH:14]([OH:16])[CH3:15])[CH2:7][OH:8]
Reactant: CC(O)C(Cc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C(CO)Cc1ccc(Cl)c(Cl)c1
Yield: 89.7 %

Procedure:
3.0 g of the alcohol compound thus obtained was dissolved in a liquid mixture of 30 ml of ethyl ether and 30 ml of tetrahydrofuran, and 1.2 g of lithium borohydride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl ether, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 2.1 g (yield: 90%) of (2RS,3RS)-2-(3,4-dichlorobenzyl)-1,3-butanediol.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH:21]([CH3:23])[CH3:22])[C:19]#[N:20].Br[CH2:25][CH2:26][CH2:27][Cl:28]>O1CCCC1>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([CH:21]([CH3:23])[CH3:22])([CH2:25][CH2:26][CH2:27][Cl:28])[C:19]#[N:20]
Reactant: ClCCCBr
Reactant: CC(C)C(C#N)c1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCCCl)c1ccccc1F
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a mixture of a 0.5 M solution of potassium bis(trimethylsilyl)amide (12.4 mL and tetrahydrofuran (44 mL) stirring at −78° under argon was added dropwise a solution of the title product of Example 8, Step (a) (1.00 g) in tetrahydrofuran (2 mL). After stirring at −78° for 0.5 hour, 1-bromo-3-chloropropane (1.3 g) was added, and the mixture was stirred while being permitted to warm to room temperature. The mixture was partitioned between diethyl ether and saturated aqueous ammonium chloride, the aqueous layer was extracted with two portions of ether, the combined organic extracts washed with brine, dried over magnesium sulfate, filtered and evaporated to give a compound (1.20 g) which was characterized by NMR, as follows: 1H NMR(CDCl3) d 7.64-7.00(m, 4H), 3.50(t, 2H), 1.24(d, 3H), 0.82(d, 3H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH2:22])[C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([NH2:22])[C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[O:4][CH2:1][CH2:2][O:3]3)=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: N[C@@H](c1ccc(Cl)cc1)c1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(c1ccc(Cl)cc1)c1ccc(C2OCCO2)cc1
Reaction time: 20 h

Procedure:
Chiral (+)-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine may be obtained in the following manner: 3.95 cm3 of ethylene glycol are poured into a suspension of 18.16 g of chiral (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochloride, in 1000 cm3 of toluene, and 0.82 g of para-toluenesulfonic acid monohydrate is added. After stirring for 20 hours at the reflux temperature, the reaction medium is cooled, washed with a saturated aqueous sodium bicarbonate solution, with water and with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue obtained is purified on a silica gel column (particle size 0.04-0.06 mm, diameter 8.4 cm, height 21.5 cm) with, as eluent, a cyclohexane/ethyl acetate (30/70 by volume) mixture, collecting 250 cm3 fractions. Fractions 23 to 30 are concentrated to dryness under reduced pressure (2.7 kpa). 1.39 g of chiral (+)-{(4-chlorophenyl)-[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine are obtained in the form of a yellow oil.
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[CH3:12][C:13]1[CH:17]=[C:16](CC(O)=O)[O:15][N:14]=1>ClCCl>[CH3:12][C:13]1[CH:17]=[C:16]([CH2:6][C:7]([Cl:9])=[O:8])[O:15][N:14]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(CC(=O)Cl)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Dimethylformamide (few drops), followed by oxalyl chloride (9.5 mL, 106 mmol) were added dropwise to a cooled (10° C.) solution of (3-methyl-isoxazol-5-yl)-acetic acid (5 g, 35.4 mmol) in dichloromethane (50 mL), and the solution was allowed to warm to room temperature. The reaction was stirred for a further 3 hours, then concentrated under reduced pressure. The residue was azeotroped with toluene to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc2[nH]ccc2c1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
tert-Butyl 4-(5-bromo-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazine-1-carboxylate (0.40 g, 1.05 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid was collected by filtration, washed with ether, and dried to give 5-bromo-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.28 g, 94.9% yield) as the dihydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16]Cl)[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1.[CH2:21]([CH:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][O:25][CH2:24][CH:23]([CH2:21][CH3:22])[CH2:26][CH2:27][CH2:28][CH3:29])[C:10]=3[OH:18])[N:8]=[C:4]2[CH:3]=1
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reactant: CCCCC(CC)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCC(CC)COCc1cc(C)cc(-n2nc3ccc(Cl)cc3n2)c1O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
2-(5-Chloro-2H-benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (5.0 g, 16 mmol) is suspended in a mixture of 2-ethylhexanol (20.0 g, 154 mmol) and acetone (5 g) and stirred at 80° C. for 15 minutes. Sodium carbonate (3.4 g, 32 mmol) is added. The slightly yellow reaction mixture is stirred at 80° C. for 3 hours and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 4.9 g of 2-(5-Chloro-benzotriazol-2-yl)-6-(2-ethylhexyloxymethyl)-4-methyl-phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[OH:10]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]=[O:10]
Reactant: OO
Reactant: Nc1c(Cl)cccc1Cl
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(Cl)cccc1Cl
Temperature: 5 °C

Procedure:
To a solution of 2,6-dichloroaniline (42.3 g, 0.26 mole) in glacial acetic acid (520 ml) in a 1 litre conical flask at room temperature, was added 100 vol hydrogen peroxide (157 ml, 1.38 mole). The flask was plugged with absorbant cotton, and set aside on a thermostatically controlled water bath at a temperature of 25°-30° C. for 70 hours. The flask was then cooled to 5° C., and the crystalline solid collected on a sintered glass funnel, washed with ethanol-pet. ether (40°-60°) (200 ml, 1:1, v/v), and dried in an oven at 90° C. The buff leaflets weighed 40.25 g (87.6%) m.p. 171°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=C(C#N)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.S(=O)(=O)(O)O.[C:24]([OH:27])(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:25]([C:24]([OH:27])=[O:26])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)Sc1ccc(Cl)cc1C=C2

Procedure:
550 Mg. 8-chloro-3-cyanodibenzo[b,f]thiepin is refluxed for 16 hours in a mixture of 15 cc. acetic acid and 15 cc. 50% aqueous sulfuric acid. The reaction mixture is cooled down and the product filtered, washed with water, and dried to yield 485 mg. (82% of the pure acid, m.p. 302°-304° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)(C)C.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[CH3:17][O:18][CH2:19][CH2:20][NH:21][C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)=[O:16]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNC(=O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 0° C. solution of 500 mg of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, 328 mg of 2-methoxyethylamine, 736 mg of HOBt, and 1.82 mL of triethylamine in 9 mL of dichloromethane was treated with 836 mg of EDC.HCl. The mixture was stirred at 25° C. overnight and the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate, and the solution was sequentially washed with water, an aqueous solution of citric acid, an aqueous sodium bicarbonate solution, and brine. The solution was dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in a 4 M solution of HCl in dioxane. After 1 h the mixture was evaporated to give 406 mg of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[O:25]1[CH:29]=[N:28][C:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)=[N:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([C:27]4[N:28]=[CH:29][O:25][N:26]=4)=[CH:36][CH:35]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2ncon2)cc1
Product: CCC(C(=O)Nc1ccc(-c2ncon2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.29 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 73 mg (0.43 mmol, 1.5 eq.) of 4-(1,2,4-oxadiazol-3-yl)aniline were reacted according to General Method 7. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 2-5% mixtures) and subsequently by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 81 mg (55% of theory)
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1([OH:33])[CH2:11][CH:10]2[C:12]([CH3:14])([CH3:13])[C:7]1([CH2:15][S:16]([N:19]1[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]1)(=[O:18])=[O:17])[CH2:8][CH2:9]2)C.[OH-].[Na+]>CO.O>[OH:33][C:6]1([CH2:5][C:4]([OH:34])=[O:3])[CH2:11][CH:10]2[C:12]([CH3:13])([CH3:14])[C:7]1([CH2:15][S:16]([N:19]1[CH2:20][CH2:21][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:23][CH2:24]1)(=[O:17])=[O:18])[CH2:8][CH2:9]2
Reactant: CCOC(=O)CC1(O)CC2CCC1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)C2CCC1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C(O)(CC(=O)O)C2
Reaction time: 4.5 h

Procedure:
(1S(1.Alpha.,2α,4.alpha))-2-hydroxy-7,7-dimethyl-1-((spiro(1H-indene-1,4'-piperidin)-1'-yl sulfonyl)methyl)bicyclo(2.2.1)heptane-2-acetic acid ethyl ester (3.8 g, 7.8 mmol) was stirred in methanol (40 ml) containing sodium hydroxide (10 ml of a 1.0M solution in water; 10 mmol) for 4.5 hrs. The mixture was evaporated to dryness in vacuo, treated with water (250 ml) and washed with ether. The aqueous layer was acidified with conc HCl and extracted with ether, and the ether layer from this extraction was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed an a silica gel column eluted with CH2Cl2 followed by 90:10:0.1:0.1 of CH2Cl2 :MeOH:HOAc:H2O. The product fractions were evaporated to dryness in vacuo, and the residue was triturated with ether and hexane and filtered to give the title compound as a solid: (mp 137.5°-139.5°).