Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2](=[CH2:19])[CH2:3][CH2:4][C:5]([NH:7][CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].[Cl-].[Na+].Cl>CN(C)C=O.O.O1CCOCC1>[Br:1][C:2](=[CH2:19])[CH2:3][CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6]
Reactant: C=C(Br)CCC(=O)NC(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: C=C(Br)CCC(=O)NCC(=O)OCC
Yield: 95 %

Procedure:
To a solution of the product of Example 3H (3.36 g, 10.0 mmol) in dimethylformamide (10 mL) was added sodium chloride (586 mg, 10.0 mmol), water (360 microliters, 20 mmol) and 4N hydrochloride acid in dioxane (0.012 mL, 0.5 mmol). The reaction vessel was Firestone purged three times and placed under a positive nitrogen pressure. The reaction mixture was heated at reflux for 24 hours and then concentrated in vacuo. The residue obtained was diluted with water (5 mL) and extracted with ether (3×15 mL). The combined organic extracts were decolorized with charcoal (0.5 g), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product (2.51 g, 95%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) 1.29 (t, 3H), 2.04 (s, 3H), 2.99 (m, 2H), 4.22 (q, 2H), 4.79 (m, 1H), 5.53 (d, 1H), 5.68 (m, 1H), 6.44 (d, 1H); IR (film) 1195, 1220, 1370, 1540, 1660, 1740, 2990, 3050, and 3300 cm-1. MS (DCI/NH3) m/e 264/266 (M+H)+, 281/283 (M+H+NH3)+. Anal. Calcd. for C9H14NO3Br: C, 40.92; H, 5.34; N, 5.30. Found: C, 42.04; N, 5.48; N, 5.26.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[C-:38]#[N:39].[K+].O>CN(C)C=O>[OH:19][C:5]1[CH:4]=[C:3]([CH2:2][C:38]#[N:39])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:6]=1
Reactant: [C-]#N
Reactant: Oc1ccc(-c2nc3cc(O)cc(CBr)c3o2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a solution of 7-(bromomethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (122 mg, 0.40 mmol) in N,N-dimethylformamide (1.5 mL) was added 18-crown-6-ether (202 mg, 0.80 mmol) and potassium cyanide (131 mg, 2 mmol). The reaction mixture was allowed to stir for 2 h and then poured into water and extracted with EtOAc. The organic extracts were washed with brine and dried over MgSO4. Evaporation and flash chromatography (50%–60% EtOAc/petroleum ether) gave (80 mg, 75% yield) of the product as a gray solid, m.p. 170–180° C.; MS m/e 265 (M−H)+. Analysis for C15H10N2O3×1.5H2O.
Reaction SMILES: CS[S:3][CH3:4].N(OC(C)(C)C)=O.N[C:13]1[C:17]([Cl:18])=[C:16]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:15]([CH3:31])[N:14]=1.O>C(Cl)Cl>[Cl:18][C:17]1[C:13]([S:3][CH3:4])=[N:14][N:15]([CH3:31])[C:16]=1[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:28])([F:27])[F:29])=[CH:21][C:20]=1[Cl:30]
Reactant: CSSC
Reactant: Cn1nc(N)c(Cl)c1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: ClCCl
Product: CSc1nn(C)c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethyl disulfide (0.14 ml) and 0.2 ml of tert-butyl nitrite were added dropwise to a solution of 0.2 g of 3-amino-4-chloro-5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methylpyrazole (18) in 5 ml of dry methylene chloride with ice cooling. The mixture was stirred at 0° C. for 30 minutes and thereafter poured into water, followed by extraction with chloroform. The organic layer was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography on silica gel, giving 0.2 g of the desired compound in the form of a light brown oil (quantitative yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].Cl[C:17]1[N:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>O.C(N)(CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]([NH:12][C:17]1[N:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)=[CH:19][N:18]=1)([CH2:9][CH3:6])[CH3:11]
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Reactant: Clc1ncc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: O
Product: CCC(C)Nc1ncc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cn1

Procedure:
2.50 g (12.4 mmol) N-(1-(4-ethynylphenyl)propan-2-yl)acetamide (I58.3), 3.0 g (12.42 mmol) 2-chloro-5-iodopyrimidine and 872 mg (1.24 mmol) bis(triphenylphosphine)dichloropalladium in 10 mL water and 10 mL sec-butylamine are stirred at r.t. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:32])[NH:27]2.B(Br)(Br)Br>>[CH3:19][C:9]1([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:12]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][C:26](=[O:32])[NH:27]3)[C:11]([OH:18])([C:14]([F:15])([F:17])[F:16])[CH2:10]1.[OH:18][C:11]1([C:14]([F:15])([F:16])[F:17])[CH2:10][C:9]([CH3:19])([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[CH:12]1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:32])[NH:27]2
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2cccc(O)c21
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 1.0 g of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 553 mg of 5-aminoquinolin-2(1H)-one. 21 mg of 5-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one as fraction 1 and 5 mg of 5-{[2,5-dihydroxy-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one as fraction 2 are obtained by reaction of 50 mg of the imine with 0.22 ml of BBr3 (1N in dichloromethane).
Reaction SMILES: [C:1]1([N:14]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]1=[O:13].[C:21]([O:29][CH:30]1[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([OH:38])[C:32]([CH3:40])([CH3:39])[CH2:31]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([O:29][CH:30]1[CH2:31][C:32]([CH3:40])([CH3:39])[N:33]([O:38][CH:10]2[C:11](=[O:12])[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:14]3[C:18](=[O:19])[CH:17]([O:38][N:33]4[C:34]([CH3:37])([CH3:36])[CH2:35][CH:30]([O:29][C:21](=[O:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:31][C:32]4([CH3:40])[CH3:39])[CH2:16][C:15]3=[O:20])[C:8](=[O:13])[CH2:9]2)[C:34]([CH3:36])([CH3:37])[CH2:35]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1N1C(=O)C=CC1=O
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CC(=O)N(c2ccccc2N2C(=O)CC(ON3C(C)(C)CC(OC(=O)c4ccccc4)CC3(C)C)C2=O)C1=O

Procedure:
The title compound is prepared from N,N'-1,2-phenylenedimaleimide and 4-benzoyloxy-1-hydroxy-2,2,6,6-tetramethylpiperidine according to the general procedure of Example 6.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>O1CCCC1>[CH3:28][O:27][C:23](=[O:26])[CH2:24][CH2:25][N:20]1[CH2:21][CH2:22][N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)[CH2:18][CH2:19]1
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)C1CCC(c2ccccc2N2CCNCC2)CC1
Solvent: C1CCOC1
Product: COC(=O)CCN1CCN(c2ccccc2C2CCC(C(C)(C)C)CC2)CC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a mixture of 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (530 mg, 1.76 mmol) produced in Example (10a) and tetrahydrofuran (2 mL) was added methyl acrylate (0.24 mL, 2.65 mmol), followed by stirring for 12 hours at an external temperature of 45° C. The reaction mixture was concentrated under reduced pressure and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 643 mg of the title compound as colorless crystals, as a mixture of diastereomers at the position of t-butylcyclohexyl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:26][C:25]3[C:16](=[CH:17][C:18]4[CH2:19][CH:20]([C:36](O)=[O:37])[N:21]([C@H:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28][CH3:29])[CH2:22][C:23]=4[CH:24]=3)[N:15]([CH3:39])[C:14]2=[O:40])=[CH:9][CH:8]=1.[CH3:45][O:46][C:47](=[O:66])[C@:48]([NH2:65])([CH3:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:66])[C@:48]([NH:65][C:36]([CH:20]1[CH2:19][C:18]2[CH:17]=[C:16]3[C:25]([O:26][C@@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([Cl:44])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[C:14](=[O:40])[N:15]3[CH3:39])=[CH:24][C:23]=2[CH2:22][N:21]1[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])=[O:37])([CH3:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1
Reactant: COC(=O)[C@@](C)(N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)O)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)N[C@@](C)(Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (31.6 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methyl ester (14.7 mg) following general procedure 0 to provide (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid methyl ester (LC-MS (m/z): 909). Title compound was prepared from (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid methyl ester (25 mg) following general procedure B. LC-MS (m/z): 893.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[O:9]>C(=O)([O-])O.[Na+]>[OH:9][C@H:8]([CH2:1][C:2]1[CH2:6][CH2:5][CH2:4][CH:3]=1)[C:7]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=O
Reactant: C=C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@H](O)CC1=CCCC1
Temperature: -30 °C
Yield: 91.7 %

Procedure:
A solution of an (R)-binaphthol-dibromotitanium complex which had been prepared in the same manner as in Example 6 was cooled to -30° C. and added with 82 mg (1 mmole) of methylenecyclopentane (manufactured by Aldrich Corp.) and 88 mg (1 mmole) of methyl glyoxylate, followed by reaction for 3 hours. Then, 10 ml of an aqueous sodium hydrogen-carbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were distilled off, and hexane was added to the residue to crystallize binaphthol. The remaining solution was purified by means of silica gel column chromatography to obtain 156 mg of methyl (R)-2-hydroxy-3-(l-cyclopentenyl)propionate. The yield was 92%.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN1CCOCC1>C(OCC)(=O)C>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: C[C@@H]1NC(=O)OC1=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCC(=O)N1C(=O)OC(=O)[C@@H]1C
Reaction time: 2 h
Yield: 65 %

Procedure:
(S)-4-methyl-2, 5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of decanoyl chloride (744 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methylmorpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes, and the resulting mixture was then stirred at the same temperature for 2 hours, the reaction mixture was treated in a similar manner as in Synthesis Process 5 of Example 8 to afford the title compound (525 mg, 65%) as a colorless clear syrup. A portion of the thus-obtained syrup was recrystallized from hexane to obtain white crystals (280 mg).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([C:22]#[C:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Rh]>[ClH:21].[C:1]12([CH2:11][NH:12][C:13](=[O:14])[C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:16]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)NCC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Reactant: [H][H]
Agent: [Rh]
Product: Cl
Product: NCCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Reaction time: 0.5 h
Yield: 117.7 %

Procedure:
A stirred suspension of tert-butyl 3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynylcarbamate (Example 6(i)) (0.34 g) and 5% rhodium on carbon was stirred under a positive pressure (2 barr) of hydrogen until no further uptake was observed. The mixture was filtered and concentrated. The residue was dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml of a 4M solution) and left to stand for 0.5 hours. The solution was concentrated and the residue triturated with ethyl acetate to afford the titled compound (0.174 g) as a beige powder.
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1.[CH2:26](N(CC)CC)[CH3:27].C([Si](C)(C)C)#C>C(#N)C.CC(O)=O.CC(O)=O.[Pd]>[C:26]([C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1)#[CH:27]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)ccc(OC)c21
Reactant: CCN(CC)CC
Agent: [Pd]
Agent: C#C[Si](C)(C)C
Solvent: CC#N
Solvent: CC(=O)O
Product: C#Cc1ccc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Temperature: 50 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of 50 mg (0.111 mmol) 4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole, 0.1 ml (0.77 mmol) triethylamine, 0.1 ml (0.7 mmol) ethinyltrimethylsilane and 5 mg palladium-II-acetate in 1 ml acetonitrile is stirred at 50° C. for 3 hours. Then the reaction mixture is cooled to room temperature and poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 17 mg of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:21][CH3:22])=[C:11]([C:13]([C:16]2[NH:17][CH2:18][CH2:19][N:20]=2)=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:25](CC)CC)C.N#CBr>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:13]2[C:16]3[N:20]([CH2:19][CH2:18][N:17]=3)[C:23]([NH2:25])=[N:12][C:11]=2[C:10]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COc1c(OCc2ccccc2)ccc(C2=NCCN2)c1N
Agent: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Temperature: 0 °C

Procedure:
A mixture of 3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (Step 6, 100 g, 336 mmol) and triethylamine (188 mL) in DCM (3 L) was cooled to 0° C. and treated with cyanogen bromide (78.4 g, 740 mmol). The reaction mixture was stirred and allowed to warm to room temperature gradually. After 16 h the reaction mixture was diluted with a solution of saturated sodium bicarbonate and extracted with DCM. The organic layer was washed three times with saturated bicarbonate solution followed by multiple washes with brine. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to give a semi solid (130 g with triethylamine salt contamination): 1H NMR (DMSO-d6) δ: 7.30-7.48 (7H, m), 5.31 (2H, s), 4.32 (2H, m), 4.13 (2H, m), 3.81 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[C:9]3[N:10]=[C:11]([C:17]4[N:21](C(C)C)[CH:20]=[N:19][N:18]=4)[S:12][C:13]=3[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)=[O:4].Br[C:28]1[CH:49]=CC2C3N=C(C4N(C(C)C)N=CN=4)SC=3CCOC=2[CH:29]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[C:9]3[N:10]=[C:11]([C:17]4[N:18]([CH:28]([CH3:49])[CH3:29])[N:19]=[CH:20][N:21]=4)[S:12][C:13]=3[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: COC(=O)c1ccc2c(c1)OCCc1sc(-c3nncn3C(C)C)nc1-2
Product: COC(=O)c1ccc2c(c1)OCCc1sc(-c3ncnn3C(C)C)nc1-2

Procedure:
The title compound was prepared by a similar procedure to 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid methyl ester using 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 instead of 8-bromo-2-(4-isopropyl-4H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. The title compound was isolated as a beige solid (0.61 g, 64%). LCMS: RT=4.71 min, [M+H]+=371
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.[F:70][C:71]([F:89])([F:88])[C:72]([NH:74][CH2:75][CH:76]1[CH2:81][NH:80][CH2:79][CH2:78][N:77]1[CH2:82][CH2:83][O:84][CH2:85][CH2:86][OH:87])=[O:73]>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]>[CH:9]1[C:8]2[C:2]([N:80]3[CH2:79][CH2:78][N:77]([CH2:82][CH2:83][O:84][CH2:85][CH2:86][OH:87])[CH:76]([CH2:75][NH:74][C:72](=[O:73])[C:71]([F:89])([F:88])[F:70])[CH2:81]3)=[N:3][C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[S:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCC1CNCCN1CCOCCO)C(F)(F)F
Reactant: ClC1=Nc2ccccc2Sc2ccccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NCC1CN(C2=Nc3ccccc3Sc3ccccc32)CCN1CCOCCO)C(F)(F)F

Procedure:
To a solution of 11-chlorodibenzo[b,f][1,4]thiazepine, prepared as described in the previous step, (2 g, crude) in dioxane (20 mL) was added Pd2(dba)3 (327 mg, 0.357 mmol), BINAP (225 mg, 0.357 mmol), triethylamine (6 mL, 42.9 mmol) and 2,2,2-trifluoro-N-((1-(2-(2-hydroxyethoxy)ethyl)piperazin-2-yl)methyl)acetamide, prepared as described as Step F, (2.4 g, crude). The resulting mixture was heated to reflux overnight under nitrogen atmosphere, filtered through CELITE™, and concentrated. The residue was purified by silica gel chromatography to provide the title compound. ESI-MS (M+1): 509 calc. for C24H27F3N4O3S 508.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11](Cl)(=O)=O>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[SH:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Product: Nc1ccc(Cl)c(S)c1
Yield: 116.9 %

Procedure:
A solution of anhydrous stannous chloride (152.5 g) in conc. hydrochloric acid (150 ml) was cooled to 0° C., and 2-chloro-5-nitrobenzenesulfonyl chloride (34.3 g) was added thereto while stirring. The resultant mixture was heated at 100° C. for 15 minutes while stirring, followed by being allowed to stand. Conc. hydrochloric acid (230 ml) was added to the reaction mixture. The precipitated crystals were collected by filtration, neutralized with a 4% aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried and concentrated to give 25.0 g of 2-chloro-5-aminothiophenol. M.P., 68.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH:23]=[CH:22][CH:21]=[C:20]3[C:24]([O:26]C)=[O:25])[C:4]=2[CH:3]=1.[OH-].[Na+]>C(O)C.CS(C)=O>[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH:23]=[CH:22][CH:21]=[C:20]3[C:24]([OH:26])=[O:25])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cccn1CCCN1c2ccccc2Sc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cl
Product: O=C(O)c1cccn1CCCN1c2ccccc2Sc2ccc(Cl)cc21
Yield: 188.1 %

Procedure:
3.99 g (10 mmol) of the compound obtained in Example 11 are dissolved in 15 ml of ethanol and 7.5 ml of dimethyl sulfoxide. 0.8 g (20 mmol) of sodium hydroxide (in 1N solution) is added and the mixture is heated under reflux for 7 hours, with stirring. After acidification with a 1N hydrochloric acid solution and customary treatment of the organic phases, 3.62 g of the expected product are obtained.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH:22]3[CH2:24][CH2:23]3)[C:18](=[O:21])[NH:19][N:20]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]([CH:22]3[CH2:24][CH2:23]3)[C:18](=[O:21])[N:19]([CH2:2][C:3]3[N:4]=[CH:5][NH:6][C:7]=3[CH3:8])[N:20]=2)=[CH:14][CH:15]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: Cc1[nH]cnc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1[nH]cnc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O

Procedure:
Analogously to the compound in Example 96A, 181 mg (1.62 mmol) of 4-hydroxymethyl-5-methyl-1H-imidazole, 381 mg (1.62 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] and 670 mg (4.85 mmol) of potassium carbonate were reacted with one another. This gave 180 mg (47% of theory) of the target compound in a purity of 76%.