Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][S:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH2:41][C:42](O)=[O:43])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:42](=[O:43])[CH2:41][N:36]([C:33]1[CH:34]=[CH:35][C:30]([S:29][CH3:28])=[CH:31][CH:32]=1)[S:37]([CH3:40])(=[O:38])=[O:39]
Reactant: CSc1ccc(N(CC(=O)O)S(C)(=O)=O)cc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(N(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide 30 mg, 0.071 mmol), 2-(N-(4-(methylthio)phenyl)methyl-sulfonamido)acetic acid (39.3 mg, 0.143 mmol), DMAP (17.44 mg, 0.143 mmol), and EDC (41.1 mg, 0.214 mmol) were dissolved in DMF (1.5 ml). The reaction was stirred at RT overnight to achieve completion. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with HCl 1N, Na2CO3 sat. sol. and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(4-(methylthio)phenyl)methylsulfonamido)-acetoxy)ethyl)pyridine 1-oxide (20 mg, 41.3% yield).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[CH2:18][C@@H:17](O)[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[I:56]>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH3:21])[C@@H:13]3[CH2:18][C@H:17]([I:56])[CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2C[C@H](O)C[C@@H]12
Reactant: CI
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2C[C@@H](I)C[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
To a stirred solution of 2-chloro-4-((3S,3aS,5R)-5-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile obtained as in example 8 (1.0 g, 3.27 mmol) in THF (40 mL) at 0° C. were added DIAD (0.8 mL, 3.96 mmol), PPh3 (1.28 g, 4.87 mmol) and methyl Iodide (0.25 mL, 3.92 mmol) and the reaction mixture was stirred at room temperature for 24 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate, water and extracted. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 5% acetone in hexane) provided the title compound (0.8 g, 59%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH2:13][O:12]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:15].CC(=O)C.C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([OH:15])[CH2:13][OH:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC2CO2)cc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 12 parts of 2-[2-(4-methoxyphenyl)-ethyl]oxirane in 1.8 parts of sulfuric acid and 160 parts of 2-propanone are added 100 parts of water. The whole is stirred for 2 days at room temperature. The reaction mixture is stirred with a sodium bicarbonate solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 1-[2-(4-methoxyphenyl)ethyl]-1,2-ethanediol as a residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][S:10]2(=[O:15])=[O:14])=[CH:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][N:19]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[O:14]=[S:10]1(=[O:15])[CH2:11][CH2:12][CH2:13][N:9]1[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=3[C:18]([C:17]([F:16])([F:28])[F:27])=[N:19]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: O=S1(=O)CCCN1Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=S1(=O)CCCN1Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
A mixture of 2-[(4-bromophenyl)methyl]isothiazolidine 1,1-dioxide (290 mg, 1.0 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (190 mg, 1.0 mmol), N,N-dimethylglycine (20 mol %, 21 mg, 0.2 mmol), copper (I) iodide (10 mol %, 19 mg, 0.1 mmol) and potassium carbonate (2 mmol, 276 mg) in dimethylsulfoxide (4 ml) was stirred at 190° C. in a microwave reactor for 30 minutes. The reaction mix was partitioned between dichloromethane (5 ml) and water (5 ml). The organic layer was added to a 5 g isolute silica sep-pak column and eluted with ethyl acetate. The solvent was removed under reduced pressure and the residue purified by mass directed auto-prep (MDAP) to give a greasy product which was partitioned between water and dichloromethane. The organic layer was dried over sodium sulphate and evaporated in air to give the title compound as a yellow oil (103 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:10]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=3[C:12]#[N:13])[C:4]=2[CH:3]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[C:15]([C:18]([F:20])([F:21])[F:19])[CH:16]=[CH:17][C:10]=1[N:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:22]=[C:23]([S:25]([Cl:24])(=[O:27])=[O:26])[C:2]([F:1])=[CH:3][C:4]1=2)#[N:13]
Reactant: O=S(=O)(O)Cl
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2ccc(F)cc21
Solvent: ClCCl
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a vial charged with 2-(6-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)benzonitrile (1.85 g, 5.74 mmol) was added DCM (23 mL). The resulting solution was cooled in an ice water bath prior to the addition of chlorosulfonic acid (1.526 ml, 22.96 mmol), faster than dropwise. After 30 min of stirring LC-MS of the resulting yellow/brown solution indicated desired product mass as the main mass (M+23) with consumption of starting material. The solution was added to ice water, and extracted 2× with DCM. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 25 g SNAP column ramping EtOAc in heptane (0-25%, then isocratic at 25%, 10% DCM throughout) providing product as a white foam 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (1.80 g, 4.28 mmol, 74.5% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.87-3.94 (m, 2 H) 4.40-4.49 (m, 2 H) 6.37 (d, J=11.15 Hz, 1 H) 7.50 (d, J=6.46 Hz, 1 H) 7.64 (d, J=8.51 Hz, 1 H) 7.94-8.01 (m, 1 H) 8.09 (dd, J=1.57, 0.59 Hz, 1 H). m/z (ESI) 443.1 (M+Na)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=O)[CH2:10][CH2:9]2)[C:6]2[C:16]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]=3[N:18]=[CH:19][C:5]=2[C:4](=[O:31])[NH:3]1.Cl.[F:33][C:34]([F:38])([F:37])[CH2:35][NH2:36].B.N1C=CC=CC=1C.[OH-].[Na+]>CO.C(O)(=O)C>[F:33][C:34]([F:38])([F:37])[CH2:35][NH:36][CH2:14][CH:11]1[CH2:10][CH2:9][CH:8]([N:7]2[C:6]3[C:16]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]=4[N:18]=[CH:19][C:5]=3[C:4](=[O:31])[NH:3][C:2]2=[O:1])[CH2:13][CH2:12]1
Reactant: NCC(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n([C@H]3CC[C@H](C=O)CC3)c12
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n(C3CCC(CNCC(F)(F)F)CC3)c12
Yield: 90.4 %

Procedure:
trans-4-(2,4-Dioxo-7-{[2-(trimethylsilyl)ethoxy]methyl}-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-1-yl)cyclohexanecarbaldehyde (30.4 mg, 0.0680 mmol) in a mixture of methanol (0.5 mL) and acetic acid (50 μL) was stirred with 2,2,2-trifluoroethanamine hydrochloride (12.1 mg, 0.089 mmol) and 2-picoline borane (9.50 mg, 0.089 mmol) at room temperature for 1 day. After addition of 1 M aqueous sodium hydroxide, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (ethyl acetate/hexane=1/1 (v/v)) to give the title compound as a colorless solid (32.3 mg, yield 90%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CO.C(Cl)CCl.CN(C=O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:19]([CH3:21])[CH3:20])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride (41 mg) was added to DMF (1 mL). The resulting mixture was stirred until homogeneous and then HOBt (19 mg), DIEA (65 μL), benzoic acid (17 mg) and EDC (26 mg) were added. The resulting solution was allowed to stir overnight at rt. After this time, the solution was diluted with MeOH and purified by preparative LC-MS to provide Example 75. MS found: (M+Na)+=421.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>CO>[CH3:14][O:12][C:11]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1)=[O:13]
Reactant: O=C(O)c1c[nH]c2cc(Br)ccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1c[nH]c2cc(Br)ccc12
Yield: 100 %

Procedure:
To a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, ca 9 mL) over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is redissolved in methanol and concentrated under reduced pressure. This process is repeated several times to give the title compound as a solid (100%). ES/MS m/e 256.0 (M+2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>C(O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 121.8 g (0.55 mol) of n-decyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter was separated therefrom and concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 143-145° C./0.5 Torr), yielding 90 g of 4-n-decyloxyphenyl bromide.
Reaction SMILES: Br.C[O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:15][CH2:16][N:17]=3)[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.[S-2].[Na+].[Na+]>CN1CCCC1=O>[NH2:14][C:10]1[N:9]2[CH2:15][CH2:16][N:17]=[C:8]2[C:7]2[CH:6]=[CH:5][C:4]([OH:3])=[CH:13][C:12]=2[N:11]=1
Reactant: COc1ccc2c(c1)N=C(N)N1CCN=C21
Agent: Br
Agent: [Na+]
Agent: [S-2]
Solvent: CN1CCCC1=O
Product: NC1=Nc2cc(O)ccc2C2=NCCN12
Temperature: 160 °C

Procedure:
8-Methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 3, 1.00 g, 0.002 mol) was dissolved in 1-methyl-2-pyrrolidinone (20 ml) and treated with sodium sulfide (0.76 g, 0.010 mol) and heated to 160° C. for 5 h. It was cooled, filtered from reaction rinsing with EtOAc. The solid was dissolved in a minimal amount of water and brought to pH=1 with 2N HCl, then back to pH=7 with 1N NaOH and filtered.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6](=O)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4]1.Cl.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>C(O)C>[CH3:1][O:2][C:3]1([C:6]2[CH:7]=[C:8]([NH2:9])[N:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:20])=[CH:13][CH:14]=3)[N:19]=2)[CH2:5][CH2:4]1
Reactant: COC1(C(=O)CC#N)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COC1(c2cc(N)n(-c3ccc(C)cc3)n2)CC1
Yield: 53 %

Procedure:
Heat a mixture of 3-(1-methoxy-cyclopropyl)-3-oxo-propionitrile (Preparation 2, 3.55 g, 25.5 mmol) and p-tolylhydrazine hydrochloride (12.15 g, 76.5 mmol) in ethanol (50 mL) at 90° C. in a sealed tube for 18 hours. After removal of the solvent, subject residue to silica gel chromatography eluting with 0-5% methanol in dichloromethane to give the title compound as a yellow solid (3.29 g, 53% yield, ES+(m/z) 244.2 [M+H]).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]2[N:44]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[O:11])[C:5]=3[N:43]=2)[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(C(=O)N2CCCC2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C(=O)N2CCCC2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-(pyrrolidine-1-carbonyl)-cyclohexanone (58 mg, 0.23 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (64 mg, 0.17 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (55 mg, 73%). MS ISP (m/e): 433.3 (100) [(M+H)+]. mp 94-95° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][C:31]([F:34])([F:33])[C:30](=[O:35])[NH:29][C:28]=2[CH:36]=1.Cl.O1CCOCC1>>[F:34][C:31]1([F:33])[C:30](=[O:35])[NH:29][C:28]2[CH:36]=[C:24]([NH:23][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[O:10][C:3]=34)[CH:25]=[CH:26][C:27]=2[O:32]1
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Reactant: Nc1ccc2c(c1)NC(=O)C(F)(F)O2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(-c2cc3nccc(Nc4ccc5c(c4)NC(=O)C(F)(F)O5)c3o2)cc(OC)c1OC
Temperature: 150 °C
Yield: 25.9 %

Procedure:
To a 10 mL microwave vial with stirbar was added 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (25.00 mg; 0.08 mmol; 1.00 eq.) and 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one (16.43 mg; 0.08 mmol; 1.05 eq.). The vial was sealed and flushed with N2 and the reagents were dissolved in NMP (1.00 ml). Hydrogen chloride in dioxane (0.02 ml; 4.00 M; 0.08 mmol; 1.05 eq.) was added and the reaction mixture was heated to 150° C. in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and quenched with NaOH(aq), extracted with EtOAc, dried (MgSO4) and concentrated on a rotary evaporator. The crude mixture was purified by Biotage chromatography (2-10% MeOH/CH2Cl2 15 column vol.; 10% MeOH/CH2Cl2 5 column vol.) to afford the title compound as a beige solid (10 mg, 26%). (HPLC (method F): 90%, RT: 4.69 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 11.99 (s, 1H), 9.14 (s, 1H), 8.17 (d, J=5.5, 1H), 7.57 (s, 1H), 7.35 (d, J=8.8, 1H), 7.22 (s, 2H), 7.08-7.00 (m, 2H), 6.88 (d, J=5.5, 1H), 3.85 (s, 6H), 3.72 (s, 3H); MS (m/z) 484 [M+H]+, RT: 2.9 min.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:24]=[C:23]([O:25]CC2C=CC=CC=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([C:8]1[CH:24]=[C:23]([OH:25])[C:11]2[CH2:12][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(COc1ccccc1)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(COc1ccccc1)C2
Reaction time: 72 h
Yield: 100.7 %

Procedure:
10% Pd on Carbon (50 mg) was added to a solution of 4-benzyloxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214a) (500 mg, 1.16 mmol) in EtOAc (10 mL). The mixture was stirred under H2 balloon for 3 days. The mixture was filtered through Celite and concentrated to give a colorless oil (400 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.22-7.32 (m, 2 H) 7.18 (s, 1 H) 7.04 (s, 1 H) 6.91-6.95 (m, 2 H) 6.85 (d, J=7.58 Hz, 1 H) 5.18-5.28 (m, 1 H) 4.09-4.17 (m, 2 H) 3.38 (dd, J=16.17, 9.60 Hz, 1 H) 3.15 (dd, J=16.29, 6.69 Hz, 1 H) 1.58 (s, 9 H); LCMS for C20H22O5 m/z 365.00 (M+Na)+.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:65][C@H:66]([C:71](O)=[O:72])[CH2:67][CH:68]([CH3:70])[CH3:69])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:65][C@@H:66]([CH2:67][CH:68]([CH3:70])[CH3:69])[C:71]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:72]
Reactant: CCCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.1 %

Procedure:
To a solution of propyl 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (19, 180 mg, 0.42 mmol), DCC (105 mg, 0.50 mmol) and DMAP (6 mg, 0.042 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (148 mg, 0.42 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (210 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 120 mg (53%) of the title compound as a colorless semi solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][NH2:14])[CH:6]=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10].[CH2:15]1[O:23][CH:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[OH:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12][C:5]1[CH:6]=[C:7]([CH3:11])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CCN)cc(C)c1OC
Reactant: c1ccc(C2CO2)cc1
Solvent: C1CCOC1
Product: COc1cc(CCNCC(O)c2ccccc2)cc(C)c1OC

Procedure:
1-Phenyl-7,8-dihydroxy-9-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is obtained by treating 2-(3,4-dimethoxy-5-methylphenyl)ethylamine in tetrahydrofuran with styrene oxide for 12 hours as described above to give N-[(2-hydroxy-2-phenylethyl)]-2-(3',4'-dimethoxy-5-methylphenyl)ethylamine which on cyclization gives the 7,8-dimethoxy benzazepine. Cleavage of this as described gives the desired 6-methyl compound as the hydrobromide which may be converted via the free base to the hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([Br:24])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2sccc2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2sc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (240 mg, 1.0 mmol) in acetonitrile (5 ml) cooled to 0° C. is added NBS (183 mg, 1.03 mmol, 1.03 eq.). The mixture is stirred at rt overnight. The organic phase is collected, washed with water (10 ml) and brine (10 ml), dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (hexane/EtOAc 10:1) to give the title compound. MS (+VE) m/z 318.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[C:5]([NH2:15])=[CH:4][C:3]1=2.[OH-].[K+].[C:19](=S)=[S:20]>O>[CH3:13][C:9]1([CH3:12])[CH2:10][CH2:11][C:2]([CH3:16])([CH3:1])[C:3]2[C:8]1=[CH:7][C:6]1[N:14]=[C:19]([SH:20])[NH:15][C:5]=1[CH:4]=2
Reactant: CC1(C)CCC(C)(C)c2cc(N)c(N)cc21
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc3[nH]c(S)nc3cc21
Yield: 87.3 %

Procedure:
21.8 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2,3-naphthalenediamine were suspended in 120 ml of alcohol in a 250 ml sulfonation flask equipped with stirrer, thermometer, dropping funnel and reflux condenser. There were added dropwise thereto firstly a solution of 6.3 g of potassium hydroxide in 20 ml of water and, after stirring at room temperature for 1 hour, 8.9 g (d=1.2705) of carbon disulfide. After an additional hour, the solution was stirred and then boiled at reflux overnight. After adding 11.3 g of potassium hydroxide in 45 ml of water, the mixture was stirred for an additional 1 hour. The hot solution was then filtered through a carbon filter and the filtrate was diluted with 120 ml of water. To this was added dropwise at 60°-70° C. 60 ml of 50% acetic acid and the mixture was stirred at this temperature for an additional 1 hour. The cold suspension was suction filtered and the material on the suction filter was recrystallized from isopropanol. There were obtained 22.7 g (87.5% of theory) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1H-naphth(2,3-d)imidazole-2-thiol of melting point above 300° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]=[C:11]([S:18][CH3:19])[S:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:28])C.N>>[CH2:1]([N:8]1[C:9]2[N:10]=[C:11]([S:18][CH3:19])[S:12][C:13]=2[C:14](=[O:15])[O:16][C:17]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(SC)nc1NCc1ccccc1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Agent: N
Product: CSc1nc2c(s1)c(=O)oc(=O)n2Cc1ccccc1

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 139A for the product of Example 3A (0.048 g, 92%). MS (DCI/NH3) m/z 324 (M+NH4)+.