Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][CH:4]=[N:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:61])([CH2:31][C:32]2[N:33]([C:42]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:34]=[C:35]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:36]=2)[CH:28]([F:30])[F:29])=[CH:23][CH:22]=1.[F-].[Cs+]>O1CCCC1.[Pd](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>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][C:35]1[N:36]=[C:32]([CH2:31][C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)=[CH:22][CH:23]=2)([OH:61])[CH:28]([F:29])[F:30])[N:33]([C:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:34]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(Br)cc2)C(F)F)n1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccc(C(O)(Cc2nc(CC(C)(C)C)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C(F)F)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (49 mg, 0.07 mmol) was added to a degassed, ambient temperature solution of 1-methyl-5-(tributylstannyl)-1H-pyrazole (259 mg, 0.70 mmol) and 2-(4-bromophenyl)-3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1-difluoropropan-2-ol (483 mg, 0.77 mmol) in tetrahydrofuran (15 mL). After stirring at 75° C. overnight, the reaction mixture was cooled and cesium fluoride (50% on celite) was added. After stirring vigorously at ambient temperature for 1 h, the reaction mixture was filtered, rinsing with ethyl acetate. The filtrate was washed with water, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1-difluoro-2-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]propan-2-ol.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][CH2:8][CH2:9][N:10]1[C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[C:13]([C:25]#[C:26][CH:27]2[CH2:29][CH2:28]2)([C:21]([F:24])([F:23])[F:22])[O:12][C:11]1=[O:30])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]2[N:10]([CH2:9][CH2:8][CH2:7][C:6]([OH:31])=[O:5])[C:11](=[O:30])[O:12][C:13]([C:25]#[C:26][CH:27]3[CH2:28][CH2:29]3)([C:21]([F:22])([F:23])[F:24])[C:14]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)CCCN1C(=O)OC(C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCCN1C(=O)OC(C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To 290 mg (0.63 mmol) of 2 was added 6 mL of dichloromethane and 6 mL of trifluoroacetic acid. The reaction mixture was allowed to stir at room temperature for 30 minutes and concentrated under reduced pressure. To the residue was added 40 mL of dichloromethane, which was subsequently concentrated under reduced pressure. The above process of addition of dichloromethane and concentrating under reduced pressure was repeated four more times to give 240 mg (0.59 mmol, 94% yield) of 3 as a thick gum (M+H, 402).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]#[N:37])=[C:30]([Br:38])[CH:29]=3)=[CH:24][CH:23]=2)[CH3:20])=[O:18])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:39]=[N+:40]=[N-:41].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[NH:41][N:40]=[N:39][N:37]=4)=[C:30]([Br:38])[CH:29]=3)=[CH:24][CH:23]=2)[CH3:20])=[O:18])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc(-c2ccc(OCc3nnn[nH]3)c(Br)c2)cc1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 72.8 %

Procedure:
A mixture of 1-benzyl-N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-N-methyl-1H-indole-3-carboxamide (1.56 g, 2.76 mmol), prepared in the previous step, sodium azide (542 mg, 8.34 mmol) and ammonium chloride (446 mg, 8.33 mmol) in 30 mL of DMF was stirred under nitrogen at 100° C. for 6 h. After cooling to room temperature the reaction was diluted with 50 mL of water, made basic by the addition of 10 mL of 1 N NaOH and extracted five times with ethyl acetate. The aqueous layer was filtered and then acidified with 20 mL of 1 N HCl. An oil precipitated. The aqueous layer was decanted and the oil partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (1.22 g, 72%) as a light yellow foam, MS (ESI) m/z 607 [M+H]+. Elemental Analysis for C32H27BrN6O2.0.08 H2O: Calc'd: C, 63.12; H, 4.50; N, 13.80; Found: C, 61.37; H, 4.65; N, 12.89.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10][CH2:9]2.Cl.[NH2:19][OH:20].CCN(CC)CC>CO.CCOC(C)=O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[N:19][OH:20])[CH2:11][CH2:10][CH2:9]2
Reactant: NO
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc2c(c1)CCCC2=NO

Procedure:
A solution of 6-(2-dimethylamino-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.53 g, 2.3 mmol), hydroxylamine hydrochloride (Riedel DeHaen, 0.69 g, 10.0 mmol), and Et3N (Aldrich, 1.4 mL, 10.0 mmol) in MeOH (6 mL) was heated to reflux overnight. The reaction mixture was diluted with EtOAc (70 mL) and washed with 10% Na2CO3, brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo to afford the product as an off-white solid. MS (ESI): 249 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>C1C=CC=CC=1.C(O)C.[Pd].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.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>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Nc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Nc1ccc(-c2ccccc2Cl)cn1
Yield: 97.7 %

Procedure:
A suspension of 70 mg (0.06 mmol) of tetrakis(triphenylphosphine) palladium(0) in benzene (4 ml) was treated at RT under an argon atmosphere successively with 0.35 g (2 mmol) of 2-amino-5-bromo-pyridine, 2.2 ml (4.4 mmol) of 2 M aqueous Na2CO3 solution, 0.34 g (2.2 mmol) of 2-chlorophenylboronic acid in ethanol (1 ml) and heated to reflux for 24 h. The reaction mixture was cooled and partitioned between EtOAc and water. The layers were separated, the organic layer dried over sodium sulphate and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc as eluent. Combination of the purified fractions and concentration in vacuo gave 0.4 g (98%) of the desired 5-(2-chloro-phenyl)-pyridin-2-ylamine as white crystalline solid. ISP mass spectrum, m/e: 205.1 (M+1 calculated for C11H9ClN2: 205).
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.COC1C=CC(C[N:50]2[C:58]3[CH:57]=[C:56](Br)[N:55]=[CH:54][C:53]=3[N:52]=[CH:51]2)=CC=1.[NH2:62][C:63]1[N:64]=[C:65]([O:71][CH:72]([CH3:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:66]([C:69]#[N:70])=[N:67][CH:68]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:50]1[C:58]2[CH:57]=[C:56]([NH:62][C:63]3[N:64]=[C:65]([O:71][CH:72]([CH3:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:66]([C:69]#[N:70])=[N:67][CH:68]=3)[N:55]=[CH:54][C:53]=2[NH:52][CH:51]=1
Reactant: CC(CN(C)C)Oc1nc(N)cnc1C#N
Reactant: COc1ccc(Cn2cnc3cnc(Br)cc32)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(CN(C)C)Oc1nc(Nc2cc3nc[nH]c3cn2)cnc1C#N
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.016 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (18 mg, 0.031 mmol) in toluene (1.5 mL) was degassed under a stream of nitrogen gas with stirring for 10 minutes. After addition of 1-(4-methoxybenzyl)-6-bromo-1H-imidazo[4,5-c]pyridine (50 mg, 0.157 mmol), 5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile in DMF (0.5 mL) (38 mg, 0.173 mmol) and caesium carbonate (102 mg, 0.314 mmol), the mixture was degassed for a further 5 minutes and then heated at 120° C. for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using a MP-TsOH cartridge, washing with methanol and then eluting with 2 M ammonia in methanol. The combined basic fractions were concentrated in vacuo. Preparative HPLC gave the title compound (10.8 mg, 0.032 mmol, 20%). 1H NMR (d6-DMSO, 400 MHz) δ 10.82 (br s, 1H), 8.75 (d, 1H, J=1.0 Hz), 8.36 (br s, 1H), 8.28 (br s, 1H), 8.21 (s, 1H), 8.15 (br s, 1H), 5.48-5.41 (m, 1H), 2.62 (dd, 1H, J=13.1, 7.1 Hz), 2.5-2.46 (m, partly obscured by DMSO, 1H), 2.19 (s, 6H), 1.41 (d, 3H, J=6.3 Hz). LC-MS (2) Rt=1.78 min; m/z (ESI−) 337 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17](O)=[O:18])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH2:23][C@H:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:23][C@H:24]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)[CH3:25])=[O:18])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2c1N(Cc1ccc(Cl)cc1)CCC2
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(Cc2ccc(Cl)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
A mixture of 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoline-8-carboxylic acid (310 mg), methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (240 mg), EDCI.HCl (210 mg), HOBt (160 mg), pyridine (0.25 mL), and DMF (3.00 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoate (129 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:18])=[N-]>CO>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[NH2:1]
Reactant: C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1N

Procedure:
To a solution of 2-amino-5-methoxy-3-nitro-benzoic acid (2 g, 9.4 mmol) in methanol (100 mL) was added slowly a saturated ethereal solution of diazomethane gas until the starting material was completely consumed (25 mL). Ether was removed under vacuum and the resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound as a yellow solid which was used directly for the next reaction.
Reaction SMILES: [Cl-].[CH2:2]([Al+:4][CH2:5][CH3:6])[CH3:3].[CH3:7][N:8]([CH3:17])[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][Li]>C1(C)C=CC=CC=1>[CH3:7][N:8]([CH3:17])[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][Al:4]([CH2:5][CH3:6])[CH2:2][CH3:3]
Reactant: [Li]Cc1ccccc1N(C)C
Reactant: CC[Al+]CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC[Al](CC)Cc1ccccc1N(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.7 %

Procedure:
7.17 g (7.5 ml; 59.5 mmol) of diethylaluminium chloride were added dropwise to a suspension, cooled to −30° C., of 8.40 g (59.5 mmol) of 2-dimethylaminobenzyllithium in 150 ml of toluene in an inert nitrogen atmosphere. After slow warming to room temperature, the mixture was stirred for 15 hours in order to complete the reaction. Filtration through a D4 frit and removal of the solvent by distillation gave 8:05 g of [2-(dimethylamino)benzyl]-diethylaluminium (36.7 mmol/62%) as a colourless liquid by slow fractional distillation from the residue.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Br.C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2sc(Nc3cccc(C(C)C)c3)nc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)c1cccc(Nc2nc3cc(O)ccc3s2)c1
Reaction time: 0.17 h

Procedure:
N-(3-isopropylphenyl)-5-methoxybenzo[d]thiazol-2-amine was charged with hydrobromic acid (45%) and subjected to microwave at 170° C. for 10 minutes. Reaction was then neutralized with sodium carbonate (saturated solution) and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give 2-(3-isopropylphenylamino)benzo[d]thiazol-5-ol. HPLC=4.63 min; MS: MH+=285.
Reaction SMILES: C12(CO)CC3CC(CC(C3)C1)C2.[C:13]12([CH2:23][CH2:24][OH:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.[Cl:26][C:27]1[C:28](F)=[CH:29][C:30](F)=[C:31]([CH:39]=1)[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33].ClC1C=C(C=CC=1F)C(NS(C)(=O)=O)=O>>[C:13]12([CH2:23][CH2:24][O:25][C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])=[CH:39][C:27]=3[Cl:26])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1ccc(F)c(Cl)c1
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CS(=O)(=O)NC(=O)c1ccc(OCCC23CC4CC(CC(C4)C2)C3)c(Cl)c1

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace adamantan-1-ylmethanol with 2-(adamantan-1-yl)ethanol and 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 3-chloro-4-fluoro-N-(methylsulfonyl)benzamide, the title compound was obtained as a colorless solid (0.43 g, 71%): 1H NMR (300 MHz, DMSO-d6) 12.06 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.93 (dd, J=8.7 Hz, 2.2 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 4.20 (t, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.93 (br s, 3H), 1.70-1.55 (m, 14H); MS (ES+) m/z 411.8, 413.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1O[CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8]CC1C=CC=CC=1.Cl.[CH3:18][NH2:19].[OH-].[Na+].Cl>O.C(O)C>[OH:8][C:7]1[C:6](=[O:16])[CH:5]=[CH:4][N:19]([CH3:18])[C:2]=1[CH3:1]
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(O)c(=O)ccn1C
Reaction time: 12 h
Yield: 31.4 %

Procedure:
2-methyl-3-(benzyloxy)-4-pyranone (10.4 g) was dissolved in water (80 mL) and ethanol (80 mL). Methylamine hydrochloride (4.9 g) was dissolved in water (50 mL) and sodium hydroxide was added (2.9 g). This solution was added to the solution of 2-methyl-3-(benzyloxy)-4-pyranone, followed by the addition of 2N sodium hydroxide (4.0 mL). This solution was placed under conditions of reflux for 18 hours. After this time, the pH of the solution was set to 1.1 with hydrochloric acid, and the solution was concentrated. Water was added (80 mL), and the sample was washed with diethyl ether. The resulting precipitate was dissolved in ethanol, and the pH was set to 7.8 with 10N sodium hydroxide. The solution was extracted three times with methylene chloride, and these aliquots were combined and dried over sodium sulfate. After decanting, the solvent was removed by rotary evaporation, resulting in an orange oil. This oil was dissolved in ethanol and hydrochloric acid, and the solvent was removed by rotary evaporation, resulting in a yellow solid. This solid was recrystallized from ethanol and diethyl ether resulting in a white powder. This solid was dissolved in ethanol (70 mL) and water (5 mL) and 5% palladium on charcoal catalyst (0.26 g) was added. The resulting mixture was placed under 1 atm. of hydrogen for 12 hours. Following filtration, the solvent was removed by rotary evaporation resulting in a white solid. This was recrystallized from ethanol and diethyl ether, resulting in a white powder (2.1 g). Proton NMR (D20): 7.79 (d, 1H), 6.89 (d, 1H), 3.79 (s, 3H). 2.38 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[C:25]([N:29]1[CH2:34][CH2:33][CH:32]([SH:35])[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([N:29]1[CH2:34][CH2:33][CH:32]([S:35][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[C:16]([C:20]([F:23])([F:22])[F:21])=[N:17][NH:18][CH:19]=5)[N:8]=[C:7]4[C:6]=3[CH:24]=2)[CH2:31][CH2:30]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)N1CCC(S)CC1
Reactant: FC(F)(F)c1n[nH]cc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4c[nH]nc4C(F)(F)F)cn2CCO3)CC1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
A mixture of 9-bromo-2-(3-trifluoromethyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (73 mg, 0.18 mmol), 1-tert-butylpiperidine-4-thiol (63 mg, 0.37 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (35 mg, 0.06 mmol) and DIPEA (125 μL, 0.73 mmol) in dioxane (3 mL) was purged with argon and heated at 100° C. for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, on a gradient 5-95%, 0.1% HCO2H in acetonitrile/water) affording 159 (56 mg, 31%). LCMS: RT 3.11 min [M+H]+ 492.1. 1H NMR (DMSO, 400 MHz): δ 8.51 (1H, d, J=2.40 Hz), 8.26-8.25 (1H, m), 8.21 (1H, s), 7.42 (1H, s), 7.31 (1H, dd, J=8.46, 2.42 Hz), 7.01 (1H, d, J=8.46 Hz), 4.47 (4H, s), 3.12-3.01 (1H, m), 3.05-2.93 (2H, m), 2.24 (2H, t, J=11.08 Hz), 1.92 (2H, d, J=12.67 Hz), 1.48-1.47 (2H, m), 1.02 (9H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>>[OH:9][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccc(Cl)cc1Cl
Product: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Temperature: 24 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
Molten 2,4-dichlorophenol (82.13 g) was added to 166 ml of ClSO3H at 37°-40° C. over a 1 hour period. After a 20 minute hold period at 37°-40° C. the mixture was cooled to 24° C. and held an additional 1 hour. The reaction mixture was then cautiously poured onto 1100 g of ice with constant agitation. Filtration, washing and drying afforded 104 g of 97.6% pure 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (C) (77% yield), mp 79°-82° C.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([C:14]3[C:15]([CH3:31])=[N:16][C:17]([C:20]4[N:24](C5CCCCO5)[CH:23]=[N:22][N:21]=4)=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:32])([CH3:3])[CH3:2].Cl>C(O)C>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([C:14]3[C:15]([CH3:31])=[N:16][C:17]([C:20]4[NH:24][CH:23]=[N:22][N:21]=4)=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:32])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Agent: Cl
Solvent: CCO
Product: Cc1nc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 50 °C
Yield: 62 %

Procedure:
To a stirred mixture of 1-isopropyl-7-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.400 g, 0.921 mmol) in ethanol (40 mL) at 50° C. was added hydrogen chloride (4 M in dioxane, 1.381 mL, 5.52 mmol). The resulting mixture was heated at 50° C. under nitrogen for 1 h. The suspension was concentrated under reduced pressure and the resulting solid was taken up in dimethylsulfoxide and purified using silica gel chromatography (0-10% ammonia saturated methanol in dichloromethane) to afford the title compound (0.200 g, 0.571 mmol, 62.0% yield) as a brown-red solid, which was further processed by recrystallization. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.10 (br. s., 1H), 8.01 (br. s., 2H), 7.92 (s, 1H), 5.26 (quin, J=6.93 Hz, 1H), 4.14 (s, 2H), 3.58 (d, J=5.08 Hz, 3H), 1.47 (d, J=6.64 Hz, 6H); MS (ESI) m/z 351.5 [M+1]+.