Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-].[Na+].CO.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][N:8]=1.CI>CN(C)C=O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:1])=[CH:9][N:8]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
28% Sodium methoxide-methanol (2.0 mL) was added dropwise to the above-obtained 2-chloro-5-hydroxypyridine (1.30 g) and methyl iodide (1.25 mL) in N,N-dimethylformamide (26 mL), followed by stirring at room temperature for 1.5 hours. The reaction mixture was partitioned by use of saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (hexane-ethyl acetate), to thereby give 2-chloro-5-methoxypyridine as a solid (1.40 g, 98%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]([O:13]CC)=[O:12])=[CH:8][C:7]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)=[N:6][C:5]=2[N:4]([CH:29]([CH3:31])[CH3:30])[N:3]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:18][CH:17]=3)=[N:6][C:5]=2[N:4]([CH:29]([CH3:31])[CH3:30])[N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2c1c(Br)nn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1nc(Br)c2c(C(=O)O)cc(-c3ccc(CN4CCOCC4)cc3)nc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of ethyl 3-bromo-1-isopropyl-6-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 g, 2.05 mmol) in EtOH (15 mL), aqueous NaOH (0.123 g, 3.08 mmol) was added and reaction mixture stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Solid obtained was filtered and azeotrope it with toluene to give the desired compound (0.8 g, 84.9%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:12][C:13]#[C:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([N:8]1[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=[CH:9]1)[C:13]#[C:14][CH3:15]
Reactant: CC#CCBr
Reactant: Clc1nccc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1cnc2ccnc(Cl)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 μg of 4-chloro-1H-imidazo[4,5-c]pyridine, 1.37 ml of 1-bromo-2-butyne, and 1.98 g of potassium carbonate were suspended in 15 ml of N,N-dimethylformamide, and the suspension was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 1.79 g of a 1:1 mixture consisting of the title compound and the compound alkylated at the 1-position was obtained from the fraction eluted with hexane-ethyl acetate (1:2).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=O.ClC1C=CC(C(Cl)=O)=CC=1>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[O:19][C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])=[N:9][N:10]=2)=[CH:17][CH:16]=1
Reactant: O=C(NNC(=O)c1sccc1Cl)c1ccc(Cl)cc1
Agent: O=C(Cl)c1ccc(Cl)cc1
Product: Clc1ccc(-c2nnc(-c3sccc3Cl)o2)cc1

Procedure:
4-Chloro-benzoic acid N′-(3-chloro-thiophene-2-carbonyl)-hydrazide: The title compound was prepared from 3-chloro-thiophene-2-carbonyl hydrazide (70 mg, 0.40 mmol) and 4-chlorobenzoyl chloride (50.5 μL, 0.40 mmol) similar to Example 84b, and yielded 130 mg (100%) of white solid. 1H NMR (DMSO-d6): 10.66 (s, 1H), 10.30 (s, 1H), 7.93 (m, 3H), 7.61 (d, J=8.79 Hz, 1H), 7.22 (d, J=5.22 Hz, 1H).
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17]2[S:18][CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=2)[C:9]1=[O:26])(C)(C)C.Cl>CCOC(C)=O>[CH3:25][O:24][C:22]([C:20]1[N:21]=[C:17]([N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]([CH2:7][C:6]([OH:27])=[O:5])[C:9]2=[O:26])[S:18][CH:19]=1)=[O:23]
Reactant: COC(=O)c1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(-n2c(=O)n(CC(=O)O)c3ccccc32)n1
Reaction time: 0.25 h

Procedure:
A solution of methyl 2-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1,3-thiazole-4-carboxylate from Step B (195 mg, 0.501 mmol) in EtOAc (3 mL) at 0° C. was saturated with HCl (g) for 5 min. After 15 min, the reaction was re-saturated with HCl for another 5 min. The mixture was concentrated in vacuo to give the title compound as a white solid. MS: m/z=334 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:11][C:5]([CH:6](O)[CH2:7][CH:8]=[CH2:9])=[CH:4][CH:3]=1.P([O-])([O-])(O)=[O:13].[K+].[K+].P(=O)(O)(O)O>O>[CH2:7]([CH:6]1[C:2]([OH:11])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:13])[CH:8]=[CH2:9]
Reactant: O=P([O-])([O-])O
Reactant: C=CCC(O)c1ccc(C)o1
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Product: C=CCC1C(=O)C=CC1(C)O
Yield: 80 %

Procedure:
In the same apparatus as in Example 1, 5-methyl-allyl-furfuryl alcohol (50 parts) and a buffer solution prepared from water (1500 parts) and dipotassium monohydrogen phosphate (1.7 parts) and adjusted to pH 5.1 with phosphoric acid were charged, and the resultant mixture was stirred at 100° C. in a nitrogen stream until the starting compound was consumed. The reaction mixture was treated as in Example 1 to give 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone in a yield of 80 %.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(#N)C>[N:19]1([CH2:2][C:3]2[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C#N)c1cc(CCl)cc(C(C)(C)C#N)c1
Solvent: CC#N
Product: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1

Procedure:
A solution of 2,2'-(5-chloromethyl-1,3-phenylene)di(2-methylpropiononitrile), (0.23 g), and 1H-1,2,4-triazole (0.35 g) in acetonitrile (2 ml) was heated under reflux for 18 h, then evaporated to dryness. The residue was partitioned between 1N aqueous potassium hydrogen carbonate solution and ethyl acetate, the organic phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography. Elution with methanol:chloroform (1:49 by volume), gave 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), identical with the product of Example 1, and further elution with methanol:chloroform (2:23 by volume, gave 2,2'-[5-(4H-1,2,4-triazol-4-ylmethyl)-1,3-phenylene]di(2-methylpropiononit rile), mp. 158°-161°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:44][C:45]#[C:46][CH:47]2[CH2:49][CH2:48]2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:44][C:45]#[C:46][CH:47]2[CH2:49][CH2:48]2)=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCC#CC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC#CC4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (20 mg, 0.0526 mmol) in 1 mL of DMF was added Cs2CO3 (21 ng, 0.063 mmol) and 3-cyclopropylprop-2-ynyl 4-methylbenzenesulfonate (intermediate AU) (20 mg, 0.079 mmol) at room temperature. After stirring for 2 h, the reaction was quenched with 1 mL of ice water. The mixture was extracted 3× with ethyl acetate (5 mL each). The combined organic layers were washed 2× with water (5 mL each) and brine prior to drying over Na2SO4. Concentration of the solution and purification of the crude product by preparative LC-MS afforded compound AV (10 mg). 1H NMR (CD3OD): δ 7.37˜7.34 (2H, m), 7.30˜7.28 (1H, dd, J=8.8, 2 Hz), 7.13˜7.11 (2H, d, J=8.8 Hz), 6.87˜6.83 (2H, d, J=8.8 Hz), 4.61 (2H, d, J=2 Hz), 4.11 (1H, d, J=9.2 Hz), 4.10˜4.04 (2H, dd, J=23.6, 14.8 Hz), 3.90˜3.87 (1H, m), 3.72˜3.68 (1H, m), 3.49˜3.39 (3H, m), 3.31˜3.28 (1H, m), 1.31˜1.24 (1H, m), 0.79˜0.75 (2H, m), 0.62˜0.59 (2H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:9][CH2:10][C:11](=[O:15])[NH:12][C:13]=2[N:14]=1)=O.C([BH-](CC)CC)C.[Li+].C(O)(=O)C.OO.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CO>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]2[S:9][CH2:10][C:11](=[O:15])[NH:12][C:13]=2[N:14]=1
Reactant: COC(=O)c1ccc2c(n1)NC(=O)CS2
Agent: CC[BH-](CC)CC
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: OO
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1CSc2ccc(CO)nc2N1
Yield: 73 %

Procedure:
To a suspension of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid methyl ester (WO 02/056882; 36.0 g, 161 mmol) in THF (240 mL) was added a solution of lithium triethylborohydride in THF (1M, 430 g, 3 eq.) at 5-10° C. over 70 min. Acetic acid (87 g, 9 eq.) was added dropwise at 10-25° C. to the brown solution. MeOH (180 mL) was added to the suspension at 20° C. The reaction vessel was then constantly cooled externally at 21-37° C. while a 5% w/w hydrogen peroxide solution (300 mL, 3 eq.) was added over 35 min, and a 10% w/w hydrogen peroxide solution (300 mL, 6 eq.) was added over further 35 min. A sat. aq sodium metabisulfite solution (147 g) was added at 24-36° C. The reaction mixture was concentrated under reduced pressure at 50° C. whereupon the product started to crystallize. MeOH was added to the suspension in three portions (3×180 mL) followed by removal of ca. 180 mL of solvent under reduced pressure after each addition. The solid was filtered, washed with water (2×150 mL) and tert-butyl methyl ether (150 ml). To the wet cake was added toluene in two portions (2×50 mL) followed by the removal of 50 mL solvent under reduced pressure at 50° C. The title compound was obtained as a light yellow solid (22.86 g, 73% yield; m.p. 120-135° C.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]#[N:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:14][OH:15])=[NH:12])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: N#CNc1ccc(C(=O)O)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N=C(NO)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
In 150 ml of methanol was dissolved 6.56 g of 4-carboxyphenyl cyanamide produced in Reference Example 26. To the solution was added, while stirring at room temperature, 6.1 g of hydroxylamine hydrochloride and 8.88 g of triethylamine. The mixture was stirred for two hours. The resulting crystalline precipitate was collected by filtration to afford 4.45 g of the title compound as a colorless crystalline product.
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)=[O:8])[CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[O:6][CH:5]=2)=[O:8])=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2coc(Br)c2)cc1N1CCN(C)CC1
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: COc1ccc(NC(=O)c2coc(-c3ccncc3)c2)cc1N1CCN(C)CC1
Yield: 18 %

Procedure:
5-bromo-N-[4-methoxy-3-(4-methyl- 1-piperazinyl)phenyl]furan-3-carboxamide (0.16 g;0.41 mmol) was stirred with 4-pyridylboronic acid (0.050 g;0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g;5 mol %) and anhydrous sodium carbonate (0.047 g;0.45 mmol) in water (8 ml) and DME (8 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml ) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 4%MeOH/CHCl3 to yield a orange oil which was triturated with hexane/Et2O. The solid that formed was collected by filtration and dried in vacuo to yield the title compound as a tan solid (0.029 g;18%), mp=103°-105° C.
Reaction SMILES: O=[C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[NH:3]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(OCC)OCC>CCO>[O:25]1[CH2:24][CH2:23][CH:22]([N:21]2[C:5]3=[N:6][C:7]([C:10]4[CH:11]=[N:12][N:13]5[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=45)=[CH:8][CH:9]=[C:4]3[N:3]=[CH:2]2)[CH2:27][CH2:26]1
Reactant: N#Cc1ccn2ncc(-c3ccc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: N#Cc1ccn2ncc(-c3ccc4ncn(C5CCOCC5)c4n3)c2c1
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
To a suspension of the compound obtained in example 2 section d (33.6 mg, 0.1 mmol) in EtOH (1.5 mL), citric acid (2 mg, 0.1 mmol) and triethyl orthoformate (340 μL, 2 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.2 mg of the desired product (41% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1)[C:9]([CH3:25])([CH3:24])[CH2:8]2)(=[O:4])=[O:3]>C(O)C.Cl.[Fe]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)[C:9]([CH3:25])([CH3:24])[CH2:8]2)(=[O:4])=[O:3]
Reactant: CC1(C)Cc2cc(S(C)(=O)=O)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC1(C)Cc2cc(S(C)(=O)=O)ccc2NC1c1cccc(N)c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 62.2 %

Procedure:
To a mixture of 6-methanesulfonyl-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (6.5 g, 18 mmol) in ethanol 95% (100 mL) and 10% hydrochloric acid (10 mL) was added iron (3.04 g, 54 mmol). The reaction mixture was stirred at 95° C. for 5 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with 30% sodium hydroxide in water (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (3.7 g, 25%) as a yellow solid: LC/MS m/e calcd for C18H22N2O2S (M+H)+: 331.45, observed: 331.1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[S:30]1[C:34]([CH:35]=O)=[CH:33][N:32]=[CH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:34]4[S:30][CH:31]=[N:32][CH:33]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1cncs1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)CC(C(=O)OC)=CC=N3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cncs2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
In 1,2-dichloroethane (15 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-benzazepine-4-carboxylate (0.50 g). To the solution were added 1,3-thiazole-5-carbaldehyde 10.43 g) and sodium triacetoxyborohydride (0.80 g), and the mixture was stirred at room temperature for 24 hours. To the mixture was added sodium triacetoxyborohydride (0.27 g), and the mixture was stirred for 6 hours. The solvent was removed under reduced pressure, the resulting residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/2→2/3) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([Si:11]([CH3:13])([CH3:12])[CH3:14])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: C[Si](C)(C)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Product: C[Si](C)(C)c1ccc(N)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A slurry of 10% wt. palladium on carbon (4.0 g) in IMS (25 mL) was added to a solution of (3-fluoro-4-nitro-phenyl)-trimethylsilane (62.0 g, 0.29 mol) in IMS (250 mL) and the reaction mixture flushed with nitrogen five times then hydrogen three times. The reaction mixture was then stirred under 3 bar pressure of hydrogen at room temperature for 4 hours. The reaction mixture was then purged with nitrogen again before filtering through a pad of Celite® with ethyl acetate washings. The filtrate was concentrated under reduced pressure to give the title compound as a light brown oil (53.0 g, quantitative). 1H NMR (CDCl3, 400 MHz) 7.16-7.09 (1H, m), 7.10 (1H, d, J=7.75 Hz), 6.81 (1H, t, J=8.16 Hz), 3.78 (2H, s), 0.26 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)CCC>C1(C)C=CC=CC=1.CO.C(Cl)Cl.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cccs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Yield: 54.7 %

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (50 mg, 0.1 mmol), tributyl(thiophen-2-yl)stannane (44.7 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) in toluene (3 mL) was heated to 102° C. for 24 h. The solid was filtered though a pad of Celite, and resulting crude material was reconstituted in MeOH/DCM (20 mL) and purified via preparative HPLC. The collected fractions were combined and stripped to dryness via rotary evaporation to yield the title compound (30 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[N:3]=1.C([Li])CCC.C1CCCCC1.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:24])[N:4]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[N:3]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1ccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (1.68 g, 8 mmol) (i.e. the product of Example 12, Step B) in tetrahydrofuran (10 mL) was cooled to −78° C. and then treated with a solution of 2 M n-butyllithium in cyclohexane (4.5 mL, 9 mmol) dropwise. The solution formed a thick precipitate and was allowed to stir for 30 minutes after the addition. To the stirred suspension, a solution of hexachloroethane (2.0 g, 8.5 mmol) in tetrahydrofuran (10 mL) was added dropwise. After 1.5 h the resulting clear solution was warmed to ambient temperature and quenched with the addition of water (20 mL). The reaction mixture was extracted with dichloromethane and dried over MgSO4. The solution was filtered and concentrated under reduced pressure to give 1.97 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].[OH-].[K+].[Na+].[Cl-]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2].CCCCCC.CCOC(C)=O.CN(C=O)C>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: [Pd+2]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 110 °C
Yield: 96.4 %

Procedure:
Under N2, a clean, dry flask was charged with p-tolyltrimethyltin (from Example 12, Step B) (5.61 g, 0.022 mol), 2-bromonitrobenzene (4.04 g, 0.020 mol), anhydrous DMF (40 mL), and palladium(II) bis(triphenylphosphine)dichloride (140 mg, 0.2 mmol), heated at 110° C. and stirred for 4 h when TLC (4:1 hexane/EtOAc) indicated disappearance of starting materials. The nearly black reaction mixture was cooled to room temperature, poured into a solution made from 100 mL 1N KOH and 100 mL sat. NaCl, and extracted with 3×150 mL EtOAc. The combined, organic layers were washed with 100 mL 1N KOH and 100 mL sat. NaCl, and then dried over anhydrous Na2SO4. After filtration, the amber solution was evaporated to dryness and then flash chromatographed over 900 mL SiO2, eluting with 2.5% EtOAc-hexane to give 4.109 g (96%) of the title compound as a light orange liquid, homogeneous on TLC (4/1 hex-EtOAc).