Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[S:3][CH3:4].Br[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[CH:9]=[O:10]>N1C=CC(C)=CC=1C.[Cu]>[CH3:19][O:18][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([S:3][CH3:4])[C:13]=1[O:14][CH2:15][CH2:16][CH3:17])[CH:9]=[O:10]
Reactant: CSSC
Reactant: CCCOc1c(Br)cc(C=O)cc1OC
Agent: [Cu]
Solvent: Cc1ccnc(C)c1
Product: CCCOc1c(OC)cc(C=O)cc1SC
Temperature: 25 °C
Yield: 12.6 %

Procedure:
50 ml (0.56 mole) of methyl disulfide in 400 ml of 2.4-lutidine was added 46 g (0.72 mole) of copper. The mixture was heated at 140° for 3 hours. The solution was cooled to room temperature and 74.90 g (0.56 mole) of 3-bromo-5-methoxy-4-propoxybenzaldehyde was then added. The mixture was refluxed for 16 hours at 175° C. The solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash column chromatography first then recrystallized from hexane to give 17.01 g (26% yield) of 3-methoxy-5-methylthio-4-propoxybenzaldehyde as a white solid. m.p. 64°-66° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1.N1C=CC=CC=1.[C:21]1([C:34](Cl)=[O:35])[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:34]([C:21]2[C:33]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:35])=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][CH:12]=[N:11][CH:10]=1
Reactant: Cc1ccc(N)cc1-c1cncnc1
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc3c2Cc2ccccc2-3)cc1-c1cncnc1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a suspension of 4-methyl-3-(pyrimidin-5-yl)aniline (0.111 g) and pyridine (0.15 ml) in dichloromethane (2 ml) was dropwise added a solution of the fluorene-1-carbonyl chloride (0.137 g) in dichloromethane (2 ml) followed by stirring for 2 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with methanol. The resulting solid was collected by filtration to give N-(4-methyl-3-(pyrimidin-5-yl)-phenyl)-9H-fluorene-1-carboxamide (0.167 g, 73.9%)
Reaction SMILES: BrC1C=CC2C3C(CCOC=2C=1)=CN(C1N(C2C=CC(F)=CC=2F)N=CN=1)N=3.Cl[C:30]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[N:33]=[CH:32][N:31]=1.[Br:42][C:43]1[CH:44]=[CH:45][C:46]2[O:55][CH2:54][CH2:53][C:52]3[C:48](=[N:49][NH:50][CH:51]=3)[C:47]=2[CH:56]=1.C(Cl)Cl>C1CCCCC1>[Br:42][C:43]1[CH:44]=[CH:45][C:46]2[O:55][CH2:54][CH2:53][C:52]3[C:48](=[N:49][N:50]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:41])[N:33]=[CH:32][N:31]=4)[CH:51]=3)[C:47]=2[CH:56]=1
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Reactant: Clc1ccccc1-n1ncnc1Cl
Agent: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(Br)cc2OCC3)c(F)c1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Clc1ccccc1-n1ncnc1-n1cc2c(n1)-c1cc(Br)ccc1OCC2
Yield: 42 %

Procedure:
9-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared similarly to 8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene from 5-chloro-1-(2-chloro-phenyl)-1H-[1,2,4]triazole (2.25 g, 10.5 mmol) and 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.9 g, 7 mmol), the crude product was subjected to flash chromatography (SiO2, gradient 0 to 60% DCM (+10% ethyl acetate) in cyclohexane) to give 9-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.3 g, 33%). LCMS RT=4.82 M+H+=442/444
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:31][CH3:32])[C@H:10]([O:27]C(=O)C)[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[N:14][N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:10]([OH:27])[C:11]1[O:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=2)=[N:14][N:15]=1)[CH2:31][CH3:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](OC(C)=O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nnc(-c2ccc(OC(F)(F)F)cc2)o1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Acetic acid (S)-2-tert-butoxycarbonylamino-1-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-butyl ester (0.61 mmol, 0.28 g) is dissolved in a mixture of THF (10 mL) and water (10 mL). Lithium hydroxide hydrate (1.22 mmol, 0.051 g) is added and the reaction mixture stirred for 2 h. The solvents are evaporated under reduced pressure and the residue transferred into a separating funnel with 300 mL ethyl acetate and 50 mL water. The phases are separated and the organic phase washed with brine (100 mL). The organic phase is then dried with magnesium sulfate. The solvent is evaporated under reduced pressure and dried under high vacuum to yield ((S)-1-{hydroxy-[5-(4-trifluoromethoxy-phenyl)-1,3,4-oxadiazol-2-yl]-methyl}-propyl)-carbamic acid tert-butyl ester as an oil (0.225 g, 89%) MS: m/z=440 (M+Na+), 418 (M+H+)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@H:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]4[O:13][C:12]3=[O:20])=[N:7][C:6]=12.[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[C:37]1[N:41]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:40]=[CH:39][N:38]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[C@H:15]5[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]5[O:13][C:12]4=[O:20])=[N:7][C:6]=23)[CH:25]=[CH:24][C:23]=1[C:37]1[N:41]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:40]=[CH:39][N:38]=1
Reactant: O=C1O[C@@H]2CCCC[C@@H]2N1c1ccn2ncc(Br)c2n1
Reactant: CC1(C)OB(c2ccc(-c3ncnn3COCC[Si](C)(C)C)c(F)c2)OC1(C)C
Product: C[Si](C)(C)CCOCn1ncnc1-c1ccc(-c2cnn3ccc(N4C(=O)O[C@@H]5CCCC[C@@H]54)nc23)cc1F
Yield: 52 %

Procedure:
(3aS,7aR)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)hexahydrobenzo[d]oxazol-2(3H)-one (17 mg, 52%) was prepared by the procedure described in Example 1, Step 8, using (3aS,7aR)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)hexahydrobenzo[d]oxazol-2(3H)-one and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[CH:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)[CH:19]([NH:21][S:42]([CH:39]4[CH2:41][CH2:40]4)(=[O:44])=[O:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)N)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1ccc(C(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)NS(=O)(=O)C2CC2)cc1
Temperature: 25 °C

Procedure:
The racemic mixture of (1RS,2SR)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine (27a, 11 mg, 0.02 mmol) was dissolved in THF (1.5 mL). Excess N-ethyldiisopropylamine (0.185 mL, 1.1 mmol) and cyclopropanesulfonyl chloride (0.063 mL, 0.62 mmol) was added in portions over a period of 3 hours. The reaction mixture was stirred over night at room temperature, quenched by addition of water and purified by HPLC. Fractions with product was freeze dried to give the title compound as a colourless solid. Chiral HPLC was made using an Chiralpak IB™, 150×0.46 mm column, 15% EtOH in iso-Hexane, 0.5 mL/min, UV=254 nm. two peaks was seen in 1:1 ratio.
Reaction SMILES: [CH2:1]=[CH:2]C(=C)C.[CH3:6][O:7][C:8]([O:12][CH2:13][C:14]#[CH:15])([CH2:10][CH3:11])[CH3:9].BrCC>CCCCCC>[CH3:6][O:7][C:8]([CH3:9])([O:12][CH2:13][C:14]#[C:15][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: C#CCOC(C)(CC)OC
Reactant: C=CC(=C)C
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC(C)(CC)OC
Temperature: -38 °C
Reaction time: 0.42 h
Yield: 89.1 %

Procedure:
890 mg (127 mmol) of granulated lithium were added within 5 minutes to 100 ml (4.0 mol) of liquid ammonia at −40° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 5.94 g (86.6 mmol) of isoprene was added portion wise within 10 minutes, whereas the solution gets white at the end of the addition. The mixture was stirred for 25 minutes at −38° C. 9.1 g (69.5 mmol) of 2-methoxy-2-prop-2-ynyloxy-butane (97.4% GC) were added with a dropping funnel to the reaction mixture at −38° C. within 25 minutes. The reaction mixture was held at −38° C. for about 1 hour. 14 g (128.5 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1 hour and 30 minutes. 50 ml of water was added to the reaction mixture at 40° C., and the mixture was stirred until all salt was dissolved. The mixture is transferred into a separatory funnel and the layers were separated. The aqueous layer is extracted with 127 ml of n-hexane. The organic layers were dried over 0.5 g of anhydrous sodium sulphate and concentrated under reduced pressure (40° C., 60 mbar), and the crude product (1-(1-methoxy-1-methyl-propoxy)-pent-2-yne) was analyzed by GC. 10.54 g of crude 1-(1-methoxy-1-methyl-propoxy)-pent-2-yne were obtained with a purity of 87.1% (yield 77.6% based on 2-methoxy-2-prop-2-ynyloxy-butane).
Reaction SMILES: C(OO)(=[O:3])C.C([O-])(=O)C.[Na+].[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1[CH:20]([OH:24])[CH2:21][CH:22]=[CH2:23].C([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl>[CH3:11][C:12]12[O:3][C:13]1([CH:20]([OH:24])[CH2:21][CH:22]=[CH2:23])[C:14]([CH3:18])([CH3:19])[CH2:15][CH2:16][CH2:17]2
Reactant: C=CCC(O)C1=C(C)CCCC1(C)C
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCC(O)C12OC1(C)CCCC2(C)C

Procedure:
A mixture of 40% peracetic acid (105 g.) and anhydrous sodium acetate (3.0 g.) was added at 25° with stirring to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene (97 g.) and anhyd. sodium acetate (60 g.) in 175 ml. of CH2Cl2 (1.5 h.). Stirring was continued for one night and 500 ml. of water were then added to the reaction mixture. The organic layer was separated and, after the usual treatments, distilled to give 98 g. (83%) of two diastereoisomers of the epoxy product.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[C:21]([N+:30]([O-:32])=[O:31])[CH:20]=1>O1CCOCC1>[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:8](=[O:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:21]([N+:30]([O-:32])=[O:31])[CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
Triethylamine (2.90 ml, 21.4 mmol) and phenyl chlorocarbonate (2.52 ml, 20.0 mmol) were added to a dioxane solution (43 ml) of 3-(4-fluoro-2-nitrophenoxy)propylamine (4.03 g, 18.8 mmol), while being cooled with ice, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane: ethyl acetate=30:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 5.92 g of powdery yellow phenyl [3-(4-fluoro-2-nitrophenoxy)propyl]carbamate (yield: 94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([N+:21]([O-])=O)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]>C1COCC1.CO.[Pd]>[NH2:21][C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:12][C:13]=2[CH:20]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21

Procedure:
2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-5-nitro-benzimidazole (5.5 g, 18 mmol) in 150 mL THF and 75 mL methanol is hydrogenated in the presence of 1.0 g of 5% Pd/C at ambient temperature under normal pressure. The catalyst is filtered off, the filtrate is evaporated, not quite to dryness, diluted with 100 mL of acetonitrile and evaporated down to a residual volume of 30 mL. The crystal slurry is cooled and filtered. The crystals are washed with cold acetonitrile and ether.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7]S[N:9]=2)[C:5]([Br:11])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[C:10]([NH2:9])=[C:6]([NH2:7])[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)c2nsnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1c(Br)ccc(Br)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The specific preparation is described as follows: dissolving 4,7-dibromo-2,1,3-benzothiadiazole in organic solvent such as ethanol, adding appropriate sodium borohydride at 0° C., then raising the temperature to room temperature, stirring for 12-24 hours, distilling organic solvent of reaction product, after adding water, washing with saline water, then extracting with diethyl ether, drying with anhydrous sodium sulfate. 3,6-dibromo-1,2-diaminobenzene is obtained after solvent is rotary dried.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1>[Cl:24][CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[O:34])=[CH:31][CH:30]=1)=[O:27]
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc(C(=O)N2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
2.18 g of 4-chlorobenzylpiperazine are dissolved in 40 ml of absolute tetrahydrofuran. With stirring, 1.73 g of Hunig base and 2.64 g of 4-chloroacetylaminobenzoic acid chloride are added thereto in succession. The internal temperature rises to approximately 38°. After 30 minutes, the solution is concentrated by evaporation. The oily residue is digested with water, yielding 1-[4-(N-chloroacetylamino)benzoyl]-4-(4-chlorobenzyl)piperazine having a melting point of 205°-207°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:5]
Reactant: NC1CCOCC1
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCOCC1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A solution of 2,6-dichloronicotinoyl chloride (4.21 g, 20 mmol) in DCM (20 mL) was added dropwise to a stirred suspension of 4-aminotetrahydropyran (2.03 g, 20 mmol) and N-ethyldiisopropylamine (4.19 mL, 24 mmol) in DCM (20 mL) at 0° C., over a period of 30 minutes under nitrogen. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 2,6-dichloro-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (5.03 g, 92%) as a white solid.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]S(C(C)(C)C)=O)[CH:20]=[CH:19][N:18]=1.Cl>C1COCC1.CO>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([CH:13]4[CH2:15][CH2:14]4)[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:19][N:18]=1
Reactant: Brc1ccnc(C2CC2)c1
Reactant: CC(C)(C)S(=O)N=C(c1ccnc(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C3CC3)c2)c2cccc(F)c21
Temperature: -100 °C
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
Under an atmosphere of argon, tert-butyllithium (1.7 M in pentane) (0.576 mL, 0.98 mmol) was added dropwise to anhydrous tetrahydrofuran (4.00 mL) at −100° C. 4-Bromo-2-cyclopropylpyridine (0.097 g, 0.49 mmol) in anhydrous THF (2.00 mL) was added dropwise to the mixture. The solution was stirred for 2 minutes before dropwise addition of a solution of N-((2-bromopyridin-4-yl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.200 g, 0.49 mmol) in anhydrous THF (2.00 mL). The reaction was stirred at −100° C. for 20 minutes, then the temperature was raised to −78° C. over a period of 10 minutes. The reaction was stirred at −78° C. for another 60 minutes. MeOH (2.0 mL) was added dropwise at −78° C. followed by hydrogen chloride (1.25 M in methanol) (1.176 mL, 1.47 mmol). The cooling bath was removed and the reaction was left to stir at ambient temperature for 60 minutes. The solvents were evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (×2), the organics were combined, dried (Na2SO4), filtered and evaporated. Purification by silica chromatography using 0 to 5% (3.5 M ammonia in methanol) in dichloromethane gave the title compound (0.094 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].ClC1C=C(C=CC=1)C(OO)=[O:41].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:25]([CH3:31])[N:26]([OH:41])[CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCN(c1cc(Cl)cnc1C(=O)C1=C(C)C=CN(O)C1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
To a solution of 4-Chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.182 mmol) in 3.5 mL of DCM was added meta-chloroperoxybenzoic acid (77%, 95 mg, 0.424 mmol). After thirty hours the crude mixture was added 1.0 ml of pyridine and the mixture was concentrated. The mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The crude was used at next step without any further purification. MS: (M+H)/z=564.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 85 °C
Reaction time: 18 h
Yield: 14.1 %

Procedure:
2-Fluoronitrobenzene (10.0 g, 70.9 mmol) was added to chlorosulfonic acid (10.0 ml, 150 mmol) at 65° C. After stirring at 85° C. for 18 h, the reaction mixture was cooled to room temperature and poured onto ice chips and extracted with CH2Cl2 (2×250 ml). The combined organic extracts were washed with saturated NaHCO3 solution and dried (MgSO4). Concentration at room temperature and then at 100° C. under high vacuum produced 2.40 g (14%) of the title compound as a yellow oil. 1H-NMR (CDCl3): δ 8.76 (1H, dd, J=2.4, 6.5 Hz), 8.33 (1H, ddd, J=2.4, 3.8, 9.2 Hz), 7.61 (1H, t, J=9.2 Hz). MS (EI): 239 (15, M+), 204 (100).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O.CC(OC)(C)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to −5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure. The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (˜6 L), 95% heptane/ethyl acetate (˜12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22]C2CCCCO2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][C:2]1[C:10]2[N:9]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:5]([CH:21]=[O:22])=[C:4]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Reactant: Oc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(COc4ccccc4)cc(C)c32)cc1

Procedure:
The title compound was prepared from (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) using phenol instead of phthalimide in the method depicted in Example 53. MS (ESI+) m/z 420.1 (M+H).