Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:38]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:16][CH:17]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:38]=1
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: CC(Cl)Cl
Product: Oc1ccc2c(Cc3ccc(CN4CCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
6-Methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-3-[4-[(1-pyrrolidinyl)methyl]benzyl]benzo[b]thiophene (35 mg, 0.066 mmol) in dichloroethane (2 mL) at 0° C. under argon was treated with ethanethiol (0.1 mL) and aluminum chloride (98 mg) for 3 h before quenching with saturated aqueous sodium bicarbonate solution (5 mL). The stirring was allowed to continue for 1 h at ambient temperature. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the title compound as a white foam (25 mg, 73%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.C([O:40][C@@H:41]([CH3:45])[C:42](Cl)=[O:43])(=O)C>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:42](=[O:43])[C@@H:41]([OH:40])[CH3:45])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]O)=[O:8])=[CH:5][CH:4]=[C:3]([F:11])[CH:2]=1.CI.[H-].[Na+].CN(C)[CH:18]=[O:19]>>[CH3:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([F:11])=[CH:2][C:1]=1[O:19][CH3:18])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(CO)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(F)ccc1C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 13.9 g. of 2-hydroxy-4-fluoroacetophenone in 75 ml. of dry dimethylformamide were added 30 ml. of methyl iodide. The solution was cooled to 0° C. and 4.1 g. of a 50% oil dispersion of sodium hydride were carefully added. After stirring for one hour at 0° C., the reaction was extracted with ethyl acetate. The organic extract was washed three times with 200 ml. each of 1N hydrochloric acid. The ethyl acetate solution was then dried and removed in vacuo. This reaction and a subsequent identical reaction provided a total of 28 g. of 2-methoxy-4-fluoroacetophenone as an oil which was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[C:11]([CH:13]([OH:18])[CH2:14][CH2:15][CH2:16]O)[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:12]=[C:11]([CH:13]2[CH2:14][CH2:15][CH2:16][O:18]2)[C:10]2[C:5](=[C:6]([C:19]([F:20])([F:21])[F:22])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: OCCCC(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1cc(C2CCCO2)c2cccc(C(F)(F)F)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of 1-(2,8-bis(trifluoromethyl)-4-quinolinyl)-4-hydroxybutanol (176 mg, 0.5 mmol) in CH2Cl2 (5 mL) was treated with p-toluenesulphonyl chloride (102 mg, 0.55 mmol) and triethylamine (0.084 mL, 0.6 mmol) and stirred at room temperature for 16 h. The mixture was poured into saturated NaHCO3 solution (10 mL), extracted with CH2Cl2 (2×10 mL) and the combined organic phase dried (MgSO4), concentrated in vacuo, purified by chromatography [SiO2, heptane-EtOAc (95:5)] and the resulting solid triturated with cold hexane and filtered to give the title compound (111 mg, 66%) as a white solid: mp 61.0-61.7° C.; IR νmax (Nujol)/cm−1 3096, 2924, 2854, 1603, 1585, 1516, 1463, 1431, 1308, 1178, 1100, 1086 and 775; NMR δH (400 MHz, CDCl3) 1.79-1.86 (1H, m), 2.00-2.16 (2H, m), 2.63-2.71 (1H, m), 4.08 (1H, q, J 7.3 Hz), 4.24-4.29 (1H, m), 5.63 (1H, t, J 7.3 Hz), 7.72 (1H, t, J 7.7 Hz), 7.99 (1H, s), and 8.14-8.18 (2H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][SH:14]>>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][S:14][CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1
Reactant: Nc1nc(CCl)cs1
Reactant: COC(=O)CCS
Product: COC(=O)CCSCc1csc(N)n1
Yield: 59.7 %

Procedure:
3-(2-Amino-thiazol-4-ylmethylsulfanyl)-propionic acid methyl ester (0.75 g, 60%) was prepared from 4-chloromethyl-thiazol-2-ylamine (1.00 g, 5.41 mmol) and 3-mercapto-propionic acid methyl ester (0.97 g, 8.11 mmol) according to procedure Z.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.COCCOC.N>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: N
Solvent: O
Solvent: COCCOC
Product: Nc1cccc2c1C(=O)c1cc([N+](=O)[O-])ccc1C2=O
Yield: 93 %

Procedure:
A mixture of 301 g of 1,7-dinitroanthraquinone (99%) and 1 liter of ethyleneglycol dimethylether was reacted with 510 g of ammonia in an autoclave over a period of 4 hours at a temperature of 130° C. (molar ratio 30 : 1; pressure 60 atms). After cooling, the reaction mixture was poured into 5 litres of water and the deposit which precipitated was filtered off under suction, washed with water and dried. Yield: 264 g of a 93% 1-amino-7-nitroanthraquinone (91% of the theoretical yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>O1CCOCC1>[NH2:37][S:34]([NH:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)(=[O:36])=[O:35]
Reactant: NS(N)(=O)=O
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNS(N)(=O)=O)(c2ccc(F)cc2)OC1=O
Yield: 25 %

Procedure:
A mixture of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro phenyl)-1,3-oxazinan-2-one (40 mg, 0.09 mmol) and sulfamide (44 mg, 0.45 mmol) in 1,4-dioxane (10 mL) was heated to reflux overnight. When the reaction was over, the solvent was removed to give the residue, which was purified by preparative HPLC to give the desired product (12 mg, 25%). 1H NMR (CDCl3): 1.54 (m, 3H), 2.26 (m, 5H), 3.08 (m, 3H), 4.56 (s, 2H), 5.67 (m, 1H), 6.89 (m, 2H), 7.05 (m, 4H), 7.28 (m, 5H). LC-MS Method 3 tR=1.24 min, m/z=534.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:7]=1.[NH2:19][CH2:20][CH:21]=[CH:22][C:23]([OH:25])=[O:24].C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8](=[N:19][CH:20]=[CH:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1O
Reactant: NCC=CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)cc(C(=NC=CCC(=O)O)c2ccc(Cl)cc2)c1O

Procedure:
In a 1-l round-bottomed flask, 15.3 g (0.054 mole) of (5-chloro-2-hydroxy-3-methylphenyl)(4-chlorophenyl)methanone, 5 g (0.049 mole) of 4-amino-2-butenoic acid and 4.5 g (0.054 mole) of sodium hydrogencarbonate are introduced in 700 ml of methanol. The mixture is evaporated to dryness on a water bath at 100° C. under reduced pressure. The operation is repeated seven times, evaporating 500 ml of methanol at a time. The dry residue is taken up with 200 ml of methylene chloride and 300 ml of water, acidified to pH 4 with 3.7 g of citric acid and then extracted with l of methylene chloride. The organic phase is washed with water, decanted, dried over MgSO4, filtered and evaporated to dryness. The compound is crystallised in 100 ml of hexane, filtered, drained and dissolved in 100 ml of ethyl acetate. The product crystallises slowly. It is filtered, drained and washed with 10 ml of ether.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[NH:7][C:6]1=[O:27])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl>C(OCC)(=O)C.O>[C:1]([O:4][C@H:5]1[C@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[N:7]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[C:6]1=[O:27])(=[O:3])[CH3:2]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2SC(c3ccccc3)=C(C)NC(=O)[C@H]2OC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2SC(c3ccccc3)=C(C)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A mixture of 2.3 g (0.006 mol) of trans-rac.-6-(acetyl-oxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-2-phenyl-1,4-thiazepin-5(4H)-one, 1.0 g (0.0072 mol) of powdered potassium carbonate, and 0.8 g (0.0066 mol) of 2-dimethylaminoethyl chloride in 50 ml of ethyl acetate was stirred and heated at reflux for 2 hours, then twice an additional 0.3 g of dimethylaminoethyl chloride was added at 2 hour intervals. The mixture was heated at reflux for a total of 2 hours, then cooled to room temperature and diluted with water. The organic phase was separated, washed with brine and dried (MgSO4) and the solvent was removed under reduced pressure. The residue was crystallized from ether to give 1.7 g (70%) of trans-rac.-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-4-[2-(dimethylamino)-ethyl]-2-phenyl-1,4-thiazepin-5(4H)-one, mp 119°-120°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[F:15][C:16]([F:26])([F:25])[CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl.S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([F:15])([F:25])[F:26])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCC(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCCCC(OC(=O)c1ccc2cc(O)ccc2c1)C(F)(F)F
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-6-carboxynaphthalene (1 g) and optically active 1,1,1-trifluoro-2-octanol (1.1 g) in methylene chloride (50 ml) was added a few drops of conc. sulfuric acid and the mixture was refluxed under stirring for about two days.
Reaction SMILES: Br[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:3]([OH:5])(=[O:4])[CH:2]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(O)C=Cc1ccccc1

Procedure:
5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated at room temperature with 2.7 ml of triethylamine in 20 ml of toluene. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that the (2R)-2-bromo-3-phenylpropionic acid had reacted completely to give cinnamic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11]C1C=CC(C=O)=CC=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1.CO.[BH4-].[Na+]>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11][CH2:22][C:5]1[CH:27]=[CH:26][C:25]([CH2:29][OH:28])=[CH:2][CH:1]=1)=[O:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(C(=O)OCc2ccc(C=O)cc2)cc1C(C)(C)C
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)OCCc2ccc(CO)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (5 mmol) of the aldehyde obtained in Example 45, 50 ml of THF and 50 ml of methanol are introduced into a round-bottomed flask. 100 mg (2.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>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.[Cu]I>[Cl:16][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=1)[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15]2
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3ccccc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To 2.000 g (4.624 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 267 mg (0.231 mmole) tetrakis(triphenylphosphine)palladium(0), 88 mg (0.462 mmole) copper (I) iodide, 40 mL degassed toluene, 1.930 mL (13.87 mmole) degassed TEA, and 0.762 mL (6.94 mmole) phenylacetylene. The mixture was stirred overnight at room temperature. The mixture was concd and the resulting oil was purified using reverse phase chromatography to afford 1.648 g (88%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 1.35 (t, 3H, J=7.2 Hz), 4.27-4.39 (m, 2H), 5.83 (q, 1H, J=6.4 Hz), 7.17 (d, 1H, J=2.4 Hz), 7.34-7.37 (m, 3H), 7.45 (d, 1H, J=2.4 Hz), 7.51-7.55 (m, 2H), 7.63 (s, 1H); MS (ES+) 407 (M+1, 100); MS (EI) 406 (M+, 39), 337 (100), 309 (45).
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[C:29]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[C:29]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:28][CH:27]=[CH:26][N:25]=4)[C:19]([C:34]([F:37])([F:35])[F:36])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
Formaldehyde (37 wt % in H2O; 16.5 μL, 0.222 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (32) (22 mg, 0.044 mmol) in anhydrous methanol (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (94.0 mg, 0.444 mmol) was then added in one portion and the reaction was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (25 mL) and sat. aq. NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL), the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to yield a white solid. The solid was suspended in DCM (5 mL) and cyclohexane (20 mL) and filtered to afford the title compound (33) (16 mg, 72%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.64 (s, 1H), 8.36 (dd, J=4.8, 1.7 Hz, 1H), 7.59 (dd, J=7.7, 1.2 Hz, 3H), 7.53 (s, 1H), 7.20-7.13 (m, 3H), 7.00 (s, 1H), 3.53 (s, 2H), 3.24 (s, 4H), 2.91 (d, J=10.6 Hz, 2H), 2.47-2.39 (m, 1H), 2.24 (s, 3H), 2.12-1.99 (m, 2H), 1.78-1.59 (m, 4H). LCMS Method C: rt 1.51, 1.579 min; m/z 499 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:6][C:5]2=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:6][C:5]2=1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3c(F)cc(Br)cc3c2C1
Reactant: Fc1cccc(CBr)c1
Product: CC(C)C(=O)NC1CCc2c(c3cc(Br)cc(F)c3n2Cc2cccc(F)c2)C1
Yield: 36 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Example 96 with N-(6-bromo-8-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 19) and 3-fluorobenzyl bromide, to obtain the title compound as a white solid in 36% yield. MS (ES): m/z 461,463 (M+1), 459, 461 (M−1); HPLC (Method A): Rt=4.60 (92%).
Reaction SMILES: C([O-])=O.[NH4+].O1CCCC1.C([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][C:17]([S:23][CH3:24])=[N:18][CH:19]=2)[N:14]1[C:25]1[N:30]=[C:29]([N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=[O:37])[CH:28]=[CH:27][CH:26]=1)C=C>C(Cl)(Cl)Cl>[CH3:24][S:23][C:17]1[N:16]=[C:15]2[N:14]([C:25]3[N:30]=[C:29]([N:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]4=[O:37])[CH:28]=[CH:27][CH:26]=3)[NH:13][C:21](=[O:22])[C:20]2=[CH:19][N:18]=1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(-n2ccccc2=O)n1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CSc1ncc2c(=O)[nH]n(-c3cccc(-n4ccccc4=O)n3)c2n1
Temperature: 25 °C

Procedure:
Ammonium formate (964 mg) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)/dichloromethane complex (208 mg) were added to a tetrahydrofuran (10 mL) solution of 6′-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one (1 g), and heated overnight under reflux. The reaction liquid was cooled to room temperature, then diluted with chloroform, and washed with water and saturated saline water in order. The organic layer was dried with anhydrous magnesium sulfate. The insoluble matter was dissolved, and then the solvent was evaporated away to give crude 6′-[6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:29]([O:31][C:32](=[O:33])[C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)[CH:39]=1)[CH3:30]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
To a solution of 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4, 150 mg) in CH2Cl2 (3 ml) were added 3-ethoxycarbonylphenylboronic acid (210 mg), copper-(II)-acetate (197 mg), molecular sieve and pyridine (143 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 18 hours. The mixture was filtered, diluted with CH2Cl2 and washed with 1 M aqueous HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>1:1) to give the title compound (195 mg) as a colorless foam. MS (m/e)=564.2 [M+H+].
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=C)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=[O:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(c1)OCCc1sc(-c3ncnn3C(C)C)nc1-2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-vinyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.591 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added osmium tetraoxide (0.0473 mmol, 4% wt in water, 0.3 ml) followed by sodium metaperiodate (0.253 g, 0.00118 mol) slowly. The mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated sodium thiosulfate, then diluted with ethyl acetate and extracted 3 times with ethyl acetate. The organic phases were combined, dried with Na2SO4 and concentrated to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde. MS (ESI+) 341.1
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][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=1)=[O:28]>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[CH3:26])=[CH:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(=O)Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 4-bromoacetanilide (278 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (26 mg, 5.3%). MS (ISP) 489.3 [(M+H)+]; mp 238° C.