Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.14) (135 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (163 mg, 55%). MS (ISN) 588.2 [(M+H)+]; mp 200° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][CH:9]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:10][CH:11]([OH:17])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13].OS(O)(=O)=O>CCOCC.O>[C:1]([O:17][CH:11]([CH2:10][CH:9]([CH3:8])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCCC(C)=CCCC(C)CC(O)C(C)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(CC(C)CCC=C(C)CCC=C(C)C)C(C)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.21 h
Yield: 39.6 %

Procedure:
A flask containing 1.15 g of acetic anhydride was cooled to −10° C. with a salt-ice bath, and 3.1 g of 4 was added with magnetic stirring under an N2 atmosphere. After 10-15 min, 25 mL of concentrated H2SO4 was added. The reaction mixture was allowed to stir for an additional 10 min, after which it was diluted with 40 mL of ether and 10 mL of H2O. The mixture was extracted three times with 15 mL of saturated aqueous sodium bicarbonate and once with 10 mL of saturated aqueous NaCl. The ether layer was dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation to yield 1.40 g of a mixture of stereoisomers of the nitro acetate 5. 1H NMR δ (ppm) 5.4 (br m, CHOCOCH3), 5.2 (t, CH3C(CH3)═CH and CH2C(CH3)═CH), 4.4 (m, CHNO2), 2.1 (s, CH3CO2), 2.0 (m, C═CHCH2CH2C(CH3)═CHCH2), 1.6-1.7 (all s, CH3C(CH3)═CHCH2CH2CCH3), 1.5 (d, CH3CHNO2), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.9 (d, CH2CH(CH3)CH2).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[C:14]([C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)#[N:15]>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:19]2[CH2:18][CH2:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:14]#[N:15])[CH2:21][CH2:20]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: N#CC1(c2ccccc2)CCNCC1
Product: N#Cc1ccc(N2CCC(C#N)(c3ccccc3)CC2)c2ccccc12
Yield: 2.5 %

Procedure:
The title compound (1 mg, 3% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 4-cyano-4-phenylpiperidine (87 mg, 0.468 mmol).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([NH3+])(C)(C)C>O1CCCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(OCc2ccc(CCCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(OCc2ccc(CCCCO)cc2)c(Cl)c1=O
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To the product of Example 2E (594 mg, 1.45 mmol) was added anhydrous tetrahydrofuran (3 mL) and a 1.0 M solution of tert-butylammonium fluoride in tetrahydrofuran (2.9 mL, 2.9 mmol). The solution was stirred for 1 hour then concentrated under reduced pressure. Column chromatography [silica gel; eluent pentane-ethyl acetate (1.8:1)] provided the desired product (410 mg, 77%). 1H (CDCl3) δ(ppm): 1.61-1.64 (m, 11H); 1.67-1.74 (m, 2H); 2.68 (t, 2H); 3.68 (t, 2H); 5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C(CDCl3) δ(ppm): 27.43, 27.86, 32.56, 35.35, 62.74, 66.36, 71.88, 118.27, 125.18, 127.27, 128.99, 132.28, 143.17, 153.78, 159.07.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[C:37]([OH:39])=[O:38])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:31])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@H]1CCCN1
Product: O=C1N=C(N2CCC[C@@H]2C(=O)O)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-2-(R)-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and pyrrolidine-2-(R)-carboxylic acid following General Procedure C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:14]=2)[NH:9][CH:8]([C:4]2[CH:3]=[C:2]([NH:29][C:30]3([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]3)[CH:7]=[CH:6][CH:5]=2)[CH2:17]1
Reactant: NC1(C(=O)O)CC1
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2ccc(S(=O)(=O)N3CCOCC3)cc21
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinoline (150 mg, 0.33 mmol), copper(I) iodide (20 mg, 0.1 mmol), 1-amino-cyclopropanecarboxylic acid (135 mg, 1.3 mmol) and potassium carbonate (110 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-{3-[4,4-dimethyl-6-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-quinolin-2-yl]-phenylamino}-cyclopropanecarboxylic acid (128 mg, 80%) as a white solid: MS (ESI) M+1=486.1.
Reaction SMILES: [I-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=O)[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-:19].[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:2]([NH:9][C:10](=[O:19])[C:11]1[CH2:12][CH:13]=[CH:14][NH:17][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1ccc[n+](Cc2ccccc2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: O=C(NCc1ccccc1)C1=CNC=CC1
Yield: 72.5 %

Procedure:
To a solution of 1-benzylpyridinium-3-carboxamide iodide (1 g, 3.41 mmol) in H2O (15 mL) was added sodium carbonate (1.44 g, 13.64 mmol) and sodium dithionite (2.65 g, 12.96 mmol) at room temperature. The resulting solution was stirred under nitrogen in darkness for 15 mn. The reaction mixture was then extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure at room temperature to afford N-benzyl-1,4-dihydronicotinamide (BNAH) (0.530 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([N:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C:12]([NH:21][CH3:22])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C=O.[C:28](B)#N.[Na].C(O)(=O)C>C(#N)C>[CH3:22][N:21]([CH3:28])[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10][C:9]([N:23]([CH3:25])[CH3:24])([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: BC#N
Reactant: CNC1(c2ccccc2)CCC(c2ccc(OC)cc2)(N(C)C)CC1
Agent: C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(C2(N(C)C)CCC(c3ccccc3)(N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the title compound from Example 69 (111 mg, 0.33 mmol) and formalin (0.45 mL, 37% aqueous solution) in acetonitrile (3 mL) was mixed with sodium cyanoboron hydride (83 mg, 1.32 mmol) and stirred for 45 min at RT. Conc. acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at RT. For work up the solvent was removed in a vacuum, the residue taken up with 2N NaCl (5 mL) and then extracted with ether (3×10 mL). The organic solution was dried over Na2SO4 and concentrated to low volume in a vacuum. The remaining residue was purified by means of flash chromatography with ethyl acetate/methanol (1:2→MeOH).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]([F:19])([F:18])[C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:22]([C@:24]1([OH:31])[CH2:28][CH2:27][N:26]([CH3:29])[C:25]1=[O:30])#[CH:23]>>[F:18][C:8]1([F:19])[C:9]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:10]=2[C:4]2[CH:3]=[C:2]([C:23]#[C:22][C@:24]3([OH:31])[CH2:28][CH2:27][N:26]([CH3:29])[C:25]3=[O:30])[CH:21]=[CH:20][C:5]=2[O:6][CH2:7]1
Reactant: COC(=O)c1nc2c(s1)C(F)(F)COc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: COC(=O)c1nc2c(s1)C(F)(F)COc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Methyl 9-bromo-4,4-difluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford crude (R)-methyl 4,4-difluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Crude (R)-methyl 4,4-difluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was subjected to General Procedure M to afford 21.2 mg (38%) of 4,4-difluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxamide. M+1=420; 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (d, J=2.2 Hz, 1H), 8.15 (s, 1H), 7.49 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.43 (s, 1H), 4.76 (t, J=10.6 Hz, 2H), 3.43-3.29 (m, 2H), 2.81 (s, 2H), 2.46 (ddd, J=12.8, 6.4, 5.1 Hz, 1H), 2.26-2.15 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7](Cl)[CH:6]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:27]2[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:25]([C:24]([F:23])([F:39])[F:38])[CH:26]=2)[CH:6]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 85 °C
Yield: 59.1 %

Procedure:
To a degassed solution of [2-chloro-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-acetic acid methyl ester (165 mg, 0.5 mmol), 3,5-di(trifluoromethyl)benzeneboronic acid (160 mg, 0.6 mmol), 2N Na2CO3 (1.0 mL) in DME (9 mL) was added tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) under argon. The mixture was heated to 85° C. for 6 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (0-20% ethyl acetate in methylene chloride) to give the product as a white solid (150 mg, 59%). 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 2H), 8.24 (d, J=8.29 Hz, 2H), 7.96 (s, 1H), 7.73-7.85 (m, 4H), 3.83 (s, 2H), 3.78 (s, 3H). MS m/e 508.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:16])[C:5]2[CH:6]=[CH:7][C:8](=[O:15])[N:9]([CH2:12][CH:13]=C)[C:10]=2[CH:11]=1.O.I([O-])(=O)(=O)=[O:19].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:19])=[N+:4]([O-:16])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one 5-oxide (340 mg, 1.544 mmol) was stirred in 1,4-dioxane (16 mL) and water (8 mL) was added, followed by sodium periodate (990 mg, 2.3 eq.) and osmium tetroxide (1 mL of 4% aqueous solution). The mixture was stirred at room temperature for 3 hours. The solvents were evaporated under reduced pressure (water bath temperature 30° C.) to a volume of ca. 10 mL, and the residue was extracted with 20% methanol in DCM (v:v, 3×50 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give (7-fluoro-5-oxido-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde largely as its methyl hemiacetal) as a tan foam (327 mg). LCMS showed major peaks for the aldehyde hydrate (32%) and the methyl hemiacetal (64%).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][N:24]=1>C1COCC1>[C:5]([O:4][C:3](=[O:9])[N:2]([CH:10]1[CH2:14][CH2:13][N:12]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=2)[CH2:11]1)[CH3:1])([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.3 %

Procedure:
To a solution of commercially available tert-butyl methyl(pyrrolidin-3-yl)carbamate (1.0 g, 5.0 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with a satd. aq. NaHCO3 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate/hexanes) to afford the desired product (1.0 g, quant.) as a yellow solid. The solid was dissolved in tetrahydrofuran (50 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.5 g) and the reaction mixture was placed under an atmosphere of hydrogen (1 atm) until the reduction was complete by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (940 mg, 100%) as a red oil. ESI MS m/z 293 [C15H24N4O2+H]+
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(F)cc1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-fluoroaniline and methyl chlorooxoacetate.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[C:8]([C:17]([O:19]C)=[O:18])[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=2)[N:6]([CH3:21])[CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]([C:4]1[C:12]2[C:7](=[C:8]([C:17]([OH:19])=[O:18])[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=2)[N:6]([CH3:21])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(S(C)(=O)=O)cc2c(C(C)C)cn(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cn(C)c2c(C(=O)O)cc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
Methyl 3-isopropyl-1-methyl-5-(methylsulfonyl)-1H-indole-7-carboxylate (500 mg, 1.61 mmol) in THF/MeOH (3:1 mL) was treated with 5N NaOH (3 mL). The yellow biphasic solution was stirred at room temperature under nitrogen overnight. 6N HCl was added to pH 4 and the solution was stirred at room temperature for 2 hours. Solids were filtered and dried in vacuum-oven for 3 hours to give 3-isopropyl-1-methyl-5-(methylsulfonyl)-1H-indole-7-carboxylic acid (167 mg, 35%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (d, J=6.8 Hz, 6H) 3.15 (s, 3H) 3.27 (quin, J=6.82 Hz, 1H) 3.95-4.02 (m, 3H) 7.03 (s, 1H) 8.40 (d, J=2.02 Hz, 1H) 8.45 (d, J=1.77 Hz, 1H) MS (ES). [M+H]+ 296.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].Cl>>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 495.3 [(M+H)+]; mp 305° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=2)[O:36]1>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: COc1ccccc1C1CC(O)c2cc(O)ccc2O1
Product: COc1ccccc1C1CC(O)c2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2O1

Procedure:
2-(2-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(2-methoxyphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.49 (dd, 1H, J 7.6, 1.7 Hz), 7.34 (dt, 1H, J 8.3, 7.5, 1.7 Hz), 7.24 (d, 1H, J 2.8 Hz), 7.22 (d, 1H, J 9.1 Hz), 7.07 (d, 1H, J 8.3 Hz), 7.03 (d, 1H, J 7.5 Hz), 7.01 (dd, 1H, J 8.7, 2.8 Hz), 6.88 (d, 1H, J 8.7 Hz), 5.62 (d, 1H, J 6.3 Hz), 5.52 (d, 1H, J 10.4 Hz), 4.93-4.99 (m, 1H), 3.84 (s, 3H), 2.30-2.35 (m, 1H), 1.85-1.94 (m, 1H).
Reaction SMILES: [OH:1][C@@:2]1([CH2:14][CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][C@H:10]2[CH2:12][CH2:13][C@@H:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>CCN(C(C)C)C(C)C>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[CH2:36][CH2:37][CH2:38][N:39]([CH3:40])[CH2:15][CH2:14][C:2]1([OH:1])[CH2:11][CH:10]2[CH2:12][CH2:13][CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2c2ccccc23)cc1
Reactant: CNCCCc1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCc1nc2ccccc2[nH]1)CCC1(O)CC2CCC1c1ccccc12
Temperature: 110 °C

Procedure:
A mixture of 1000 mg of rac-toluene-4-sulfonic acid (1R*,8R*,9R*)-2-(9-hydroxy-tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-yl)ethyl ester and 508 mg of [3-(1H-benzoimidazol-2-yl)-propyl]-methyl-amine in 2 mL of DIPEA was heated to 110° C. for 30 min. The reaction mixture was cooled to rt, quenched with MeOH-water and extracted with EtOAc. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo to obtain 1.0 g as beige solid. A part of the crude product was purified by CC with EtOAc/MeOH (2:1) to obtain the desired compound as beige foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Li]CCCC.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>C1COCC1.CCCCCC>[Br:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]([OH:21])[C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1
Reactant: Brc1cccc(Br)c1
Reactant: COc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccc(Br)c2)cc1
Reaction time: 0.5 h
Yield: 1756.7 %

Procedure:
To a stirred −78° solution of m-dibromobenzene (70.9 g, 0.3 mol) in 200 mL of dry THF under Ar was added 117 mL of 2.56 M n-BuLi (0.3 mol) in hexane over 10 min. After 30 min, p-methoxybenzaldehyde (27.2 g, 0.02 mol) in 50 mL of THF was added over 20 min. The solution was stirred for 1 hr at −78° (complete by tlc) prior to quenching with saturated aq. NH4Cl. After warming to 20°, the reaction was diluted 2 fold with EtOAc prior to washing with H2O followed by brine. After drying over Na2SO4 and concentration using a rotary evaporator, 103 g of 3-bromo-4′-methoxybenzhydrol was obtained as a yellow oil that was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[NH:10][C:11]3=[O:16])[C:7]=2[C:6]([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][CH:4]=1.[CH2:28](I)[CH3:29]>>[CH2:28]([N:10]1[C:9](=[O:17])[CH:8]2[CH:12]([CH2:13][CH2:14][C:15]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([O:18][CH2:19][CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:7]=32)[C:11]1=[O:16])[CH3:29]
Reactant: CCI
Reactant: COc1ccc(OCCCc2ccccc2)c2c1CCC1C(=O)NC(=O)C21
Product: CCN1C(=O)C2CCc3c(OC)ccc(OCCCc4ccccc4)c3C2C1=O

Procedure:
Using the procedure of example 64 with the product of example 135 and ethyl iodide gave the compound; M+ 393.