Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[Br:15]N1C(C)(C)C(=O)N(Br)C1=O>C(O)(=O)C>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[C:7]([Br:15])[CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 35 °C

Procedure:
To glacial acetic acid (22.0 mL), cooled to 15° C. in a 1 L 3-n RB flask (equipped with mechanical stirrer, thermocouple, and addition funnel), was added concentrated (96%) sulfuric acid (142 mL) in one portion. An exothermic heat of solution raised the temperature to 35° C. After cooling to 25° C., 1,3-bis(trifluoro-methyl)benzene (107 g, 500 mmol) was added. With the acid mixture rapidly stirring, 1,3-dibromo-5,5-dimethylhydantoin (77.25 g; 270 mmol) was added over 2 min to give a multiple phase mixture (solid and two liquid). An exothermic reaction occured that raised the internal temperature to ˜40° C. (jacket cooling at 15° C.). After the reaction temperature began to drop (after 5 min) the reaction mixture was maintained at 45° C. for 4.5 hr.
Reaction SMILES: [N:1](=[C:3]1[CH:8]([CH3:9])[N:7]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=[O:14])[CH2:5][S:4]1)[OH:2].[CH3:15][N:16]=[C:17]=[O:18]>C(N(CC)CC)C>[CH3:15][NH:16][C:17]([O:2][N:1]=[C:3]1[CH:8]([CH3:9])[N:7]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=[O:14])[CH2:5][S:4]1)=[O:18]
Reactant: CCCCN1C(=O)CSC(=NO)C1C
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CCCCN1C(=O)CSC(=NOC(=O)NC)C1C

Procedure:
Utilizing the procedure of Example V, 2-oximino-3-methyl-4-butyltetrahydro-1,4-thiazin-5-one was reacted with methyl isocyanate in the presence of triethylamine to yield 7.0 of 2-[O-(methylcarbamoyl)oximino]-3-methyl-4-butyltetrahydro-1,4-thiazin-5-one, m.p. 118°-120° C. An nmr spectrum supported the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([N:6]2[C:10]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=3[OH:21])=[CH:9][CH:8]=[N:7]2)[CH2:3]1.CC(C)([O-])C.[K+].[S:28]1[CH:32]=[C:31]([N:33]([S:41]([C:44]2[CH:49]=[C:48]([F:50])[C:47](F)=[CH:46][C:45]=2[F:52])(=[O:43])=[O:42])C(=O)OC(C)(C)C)[N:30]=[CH:29]1.O>C(#N)C>[F:52][C:45]1[CH:46]=[C:47]([O:21][C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[C:10]2[N:6]([CH:4]3[CH2:3][N:2]([CH3:1])[CH2:5]3)[N:7]=[CH:8][CH:9]=2)[C:48]([F:50])=[CH:49][C:44]=1[S:41]([NH:33][C:31]1[N:30]=[CH:29][S:28][CH:32]=1)(=[O:43])=[O:42]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Reactant: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3cscn3)cc2F)C1
Reaction time: 0.5 h

Procedure:
2-[1-(1-Methylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenol, (Preparation 855, 137 mg, 0.00046 mol) was dissolved in acetonitrile (10 mL) and treated with potassium tert-butoxide (57 mg, 0.0005 mol) and stirred under nitrogen for 30 minutes. Tert-butyl 1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate, (Preparation 297, 182 mg, 0.00046 mol) was added and the solution stirred for 2 hours. Water (0.2 mL) was added and the solution evaporated. The residue was suspended in water and extracted with ethyl acetate (1×20 mL). The organic layer was separated and washed with brine (2×20 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated to give a foam. The foam was purified using an ISCO™ Companion (4 g. silica gel, eluting with dichloromethane:acetic acid 99.5:0.5 to dichloromethane:methanol:acetic acid 95:5:0.5). The appropriate fractions were evaporated to give a film. The film was triturated with diethyl ether to give the title compound as a white solid (11 mg).
Reaction SMILES: CN(C)C.[CH2:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH2:14][CH3:15])[C:8]=1[C:16]1[C:17](=[O:30])[CH:18]2[CH:22]([C:23]=1[OH:24])[CH2:21][CH:20]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH2:19]2)[CH3:6].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>ClCCl>[C:32](=[O:33])([O:34][CH2:35][CH3:36])[O:30][C:17]1[CH:18]2[CH:22]([CH2:21][CH:20]([CH:25]([O:26][CH3:27])[O:28][CH3:29])[CH2:19]2)[C:23](=[O:24])[C:16]=1[C:8]1[C:9]([CH2:14][CH3:15])=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[CH2:5][CH3:6]
Reactant: CCc1cc(C)cc(CC)c1C1=C(O)C2CC(C(OC)OC)CC2C1=O
Reactant: CCOC(=O)Cl
Agent: CN(C)C
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2c(CC)cc(C)cc2CC)C(=O)C2CC(C(OC)OC)CC12
Reaction time: 1 h

Procedure:
At room temperature, 80 mg (0.80 mmol) of trimethylamine are added dropwise to 0.090 g (0.25 mmol) of 2-(2,6-diethyl-4-methylphenyl)-5-(dimethoxymethyl)-3-hydroxy-4,5,6,6a-tetrahydropentalen-1(3aH)-one (compound I-a-9 according to the invention) and 30 mg (0.28 mmol) of ethyl chloroformate in 15 ml of dichloromethane, and the mixture is stirred for another 1 h. The mixture is poured onto ice-water, taken up in dichloromethane, washed with water, dried (magnesium sulphate), and the solvent is distilled off.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:22]([NH:24][O:25][CH3:26])=[O:23])=[N:5][C:6]([S:16][CH3:17])=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].I([O-])(=O)(=O)=[O:32].[Na+]>C(O)C.O>[C:1]([C:3]1[C:4]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:22]([NH:24][O:25][CH3:26])=[O:23])=[N:5][C:6]([S:16]([CH3:17])=[O:32])=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH3:10])#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(N(C)CC(C)(C)C)c2C#N)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CONC(=O)c1ccc(C)c(Nc2nc(S(C)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Temperature: 70 °C
Yield: 86.8 %

Procedure:
To a solution of 3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methylsulfanyl-pyrimidin-4-ylamino}-N-methoxy-4-methyl-benzamide (0.10 g) in ethanol (5 mL) was added the solution of sodium periodate (0.2 g) in water (1 mL). The resulting solution was heated to 70° C. for overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, and concentrated, and the residue was purified by silica gel column chromatography to afford the sulfoxide product (90 mg). MS (m/z): 445 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][C:12]#[CH:13])[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[C:15]([OH:20])(=[O:19])[CH2:16][C:17]#[CH:18]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[C:1]([O:5][C:6]([N:7]1[CH2:8][C:9]2[C:12](=[CH:13][CH:18]=[C:17]([CH2:16][C:15]([OH:20])=[O:19])[CH:10]=2)[CH2:11]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCC(=O)O
Reactant: C#CCN(CC#C)C(=O)OC(C)(C)C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2ccc(CC(=O)O)cc2C1
Temperature: 0 °C

Procedure:
A mixture of di-prop-2-ynyl-carbamic acid tert-butyl ester (4.78 g, 24.7 mmol) and ethanol (120 mL) was prepared under argon and cooled to 0° C. for 15 min. 3-Butynoic acid (3.64 g, 43.3 mmol) and tris(triphenylphosphine)rhodium (I) chloride (1.14 g, 1.23 mmol) were added and reaction was gradually warmed to room temperature over 1.3 hr. The reaction was then heated to 45° C. for 17 hr. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with 1N NaOH and extracted with diethyl ether (3×). The aqueous layer was acidified to pH ˜1 with 1N HCl and extracted with EtOAc (3×). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc:Hexane, 5-100%). ESI-MS m/z 278 (MH)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]([NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=2)([C:22]#[N:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][C:19]([C:22]#[N:23])([NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:27]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2cccc(CCl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2cccc(COCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
Sodium hydride (60% oil suspension, 191 mg, 4.77 mmol) was added to a solution of 2,2,2-trifluoro-ethanol (347 μl, 4.77 mmol) and 4-(3-chloromethyl-benzoylamino)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (600 mg, 1.59 mmol) in DMF (8 ml) at 0° C. The mixture was stirred at room temperature overnight, and then quenched with water and diluted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous NaHCO3 solution, water (×2) and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→1/2) to give 4-cyano-4-[3-(2,2,2-trifluoro-ethoxymethyl)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (366 mg, 52%).
Reaction SMILES: CN(CCN(C)C)C.[C:9]1([CH3:22])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C([Li])CCC.[CH:28]1([P:34]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)Cl)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CCCCCC.O>[C:9]1([CH3:22])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[P:34]([CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(C)c(-n2ccnc2)c(C)c1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: Cc1cc(C)c(-n2ccnc2P(C2CCCCC2)C2CCCCC2)c(C)c1
Reaction time: 1 h

Procedure:
1.6 ml of TMEDA (15 mmol.) are added to a suspension of 1.86 g (10 mmol.) of N-mesitylimidazole in 30 ml of hexane. 6.25 ml of 1.6 molar n-butyllithium solution (10 mmol.) are added at room temperature. The mixture is then heated for 2.5 hours at reflux temperature (solution 1). In another flask, 2.2 ml (10 mmol.) of dicyclohexylchlorophosphane are mixed with 20 ml of hexane and heated to 60° C. (solution 2). The boiling solution 1 is then slowly transferred into solution 2, which is at 60° C., by means of a cannula. The mixture is then boiled for a further 1 hour at reflux, the solution is cooled, and 20 ml of degassed water are added thereto. The organic phase is filtered off over magnesium sulfate. The solution is concentrated in vacua; 30 ml of pentane are added thereto, and the mixture is boiled for 1 hour at reflux. The product precipitates in crystalline form at −30° C. and is filtered off while cold. Yield: 2.48 g (65%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](OB(C2C=CC=CC=2)O)[CH:24]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[S:5][CH:6]=[C:2]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[CH:3]=3)=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: OB(Oc1cccnc1)c1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(Br)cs1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(-c2cccnc2)cs1

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide with commercially available 3-pyridylphenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 204). HPLC Ret time=1.91 min. LCMS [M+H]+ 378.22.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>S(=O)(=O)(O)O>[C:14]([NH:13][S:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:11])=[O:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1cncc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CC(=O)NS(=O)(=O)c1cncc([N+](=O)[O-])c1

Procedure:
A mixture of 0.5g. of 5-nitro- 3-pyridinesulfonamide, 2 ml. of acetic anhydride and 2 drops of conc. sulfuric acid was stirred at 90° C. for 1 hour. The solvent was then distilled off from the reaction mixture and the crystalline residue was recrystallized from ethanol to give 0.36g. of the desired product. m.p. 176° - 178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1cncc(Cl)c1
Product: CCOC(=O)c1cncc(-c2cc(OC)c(OC)c(OC)c2)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (6.36 g) and ethyl 5-chloronicotinate (6.90 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C([O-])(O)=O.[Na+]>CCO>[C:11]1([N:17]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 90.6 %

Procedure:
A mixture of 4,4,4-trifluoro-3-oxobutanenitrile (2.056 g, 15 mmol) and phenylhydrazine hydrochloride (2.169 g, 15 mmol) in EtOH was heated at 90° C. for 8 hours. The reaction was quchened with water, basified with saturated NaHCO3 solution, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as yellow solid (3.089 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 5H), 5.85 (s, 1H), 3.95 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:23]S(C(C)(C)C)=O)[CH2:17][CH2:18][O:19][CH2:20][C:21]#[N:22].Cl.C1(C)C=CC=CC=1.C[Al](C)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:17][CH2:18][O:19][CH2:20][C:21]([NH2:22])=[N:23]3)[C:6]3[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:7]=3[O:13][C:14]2=[CH:15][CH:16]=1
Reactant: CC(C)(C)S(=O)NC1(CCOCC#N)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: NC1=NC2(CCOC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a vial was added N-(7-bromo-3-chloro-5-(2-(cyanomethoxy)ethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (242 mg, 0.485 mmol) and HCl (4.0M solution in 1,4-dioxane, 0.970 mL, 3.88 mmol) in dioxane (4 mL). The mixture was stirred at RT for 20 mins, then quenched with 5 mL of a saturated aqueous solution of Na2CO3 and extracted into EtOAc. The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude product as orange oil. The crude product was dissolved with 4 mL of toluene and trimethylaluminum solution (2M in toluene, 0.728 mL, 1.455 mmol) was added to the mixture (exothermic after addition). The mixture was heated to 90° C. in oil bath for 10 min, then quenched with Rochelle's salt (12 mL) at 0° C. and stirred overnight at RT. The reaction mixture was diluted with water and extracted with EtOAc (10 mL×2). The organic extract was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered and concentrated to give the crude material as orange oil. It was absorbed onto a plug of silica gel and purified by chromatography through a gold Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 50% to 80% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane to provide (E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.22 (m, 4 H) 4.42 (s, 2 H) 6.18 (br. s., 2 H) 7.21 (d, J=8.51 Hz, 1 H) 7.39 (s, 1 H) 7.45-7.62 (m, 2 H) 8.36 (s, 1 H). The other stereoisomer is Example 3B in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1[Cl:30].[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][C:21]=2[Cl:30])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2Cl)c2ncccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice cooled (0° C.) stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.25 g, 1.1 mmol) in dry DMF (15 ml) is added sodium hydride (0.484 g of a 60% dispersion in mineral oil, 12.1 mmol). After stirring at room temperature for 3 hours, the reaction mixture is re-cooled to 0° C. and treated with 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene (5.0 g, 17.6 mmol) and sodium iodide (2.64 g, 17.6 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is poured onto water (300 ml) and extracted with 1:1 ethyl acetate/diethyl ether. The organic portions are washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:4 increasing to 1:2) to yield the titled product. (MH+ 407)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: SCc1ccccc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(SCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 80.7 %

Procedure:
86 g of 2-nitro-5-chloroaniline is dissolved in 400 ml of ethanol and the solution heated to 70° C internal temperature. An addition is made dropwise of a solution of 30.5 g of potassium hydroxide and 68 g of benzylmercaptan in 300 ml of ethanol. The reaction proceeds exothermically. Stirring is maintained overnight at the same internal temperature. The cooled mixture is stirred into ice water; the precipitate is filtered off under suction and recrystallised from ethanol to obtain 104.7 g (= 80% of theory) of 2-nitro-5-benzylthio-aniline, M.P. 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[N:20]=1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([F:25])([F:27])[F:26])=[N:22][N:23]=4)[N:20]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)nc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCO
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(Br)cn4)CC3)nn12
Temperature: 80 °C
Reaction time: 20 h
Yield: 73.4 %

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine in ethanol (7 mL) was stirred at 80° C. for 20 hours. The reaction mixture was concentrated and partitioned between dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The aqueous phase was extracted twice with dichloromethane (2×50 mL). The organic phases were combined, washed with water (100 mL), and concentrated to give a residue that was purified by flash chromatography on silica-gel using ethyl acetate as eluant to give 6-[4-(5-bromopyridin-2-yl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine 0.353 g, 73.4%)
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][C@H:16]([C:28](O)=[O:29])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][C@H:16]([C:28]([NH:64][C@H:63]([C:65]([NH2:67])=[O:66])[CH2:62][S:61][C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:29])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:31][CH:32]=1)[CH:2]=[CH2:3]
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
1.50 g (2.59 mmol) of the compound from example 11A was dissolved in 60 ml dichloromethane. 0.940 g (2.59 mmol) S-Trityl-L-cysteinamide, 0.45 ml (2.60 mmol) N,N-diisopropylethylamine and 0.984 g (2.59 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.72 g (1.64 mmol, 63% of theory, 88% purity) of the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[N:13]#[C:14]Br>CO>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[C:14]1[NH2:13]
Reactant: N#CBr
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Solvent: CO
Product: Cn1c(N)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N1-methyl-4-nitro-benzene-1,2-diamine (200 mg, 1.20 mmol) in methanol (12 ml) was added cyanogen bromide (190.1 mg, 1.79 mmol). After stirring at room temperature for 16 h, the methanol was removed in vacuo and the resulting solid was stirred with diethyl ether (40 ml) for 5 minutes. The resulting hydrobromide salt of the title compound was filtered and air-dried.