Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]4[OH:25])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]4[OH:25])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NCC4CCCCC4O)n3)c3cc(Cl)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC1CCCC[C@@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-((2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol, 14b, (0.10 g, 0.19 mmol) in THF (3 mL) was added aqueous lithium hydroxide (1 mL, of 1N solution). The reaction mixture was stirred at room temperature for 12 hours. The resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 12.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:21][C:22]([NH2:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:25][S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16])([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)N
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (3 g) in DCM (50 ml) was added 2-methylpropan-2-amine (1.73 g). The reaction was then allowed to stir at room temperature 18 h. The reaction was partitioned between H2O (100 ml) and DCM (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as colourless oil. Yield: 3.56 g
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1.C(O)(=O)C>O1CCCC1.O>[OH:29][CH:28]([C:27]1[CH:30]=[CH:31][C:24]([O:23][CH2:22][O:21][CH3:20])=[CH:25][C:26]=1[N+:32]([O-:34])=[O:33])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COCOc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1ccc(OCOC)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 105.2 %

Procedure:
1.5N butyllithium (19.3 ml, 29.0 mmole) was added under the argon atmosphere to a solution of diisopropylamine (4.3 ml, 30.6 mmole) in tetrahydrofuran (50 ml) at -78° C., and the mixture was stirred for 1 hour. Next, ethyl propiolate (2.4 ml, 23.7 mmole) and a solution of 4-methoxymethoxy-2-nitrobenzaldehyde (3.6 g, 17.0 mmole) in tetrahydrofuran (35 ml) were added in this sequence, and the reaction mixture was stirred at -78° C. for further 2 hours. After a solution of acetic acid (5.0 ml, 87.5 mmole) in tetrahydrofuran (20 ml) and water were sequentially added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(4-methoxymethoxy-2-nitrophenyl)-2-butynoate as an oil (5.53 g).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([C:15]1[C:24]2[N:25]=[CH:26][N:27]([CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O.C(OCC)(=O)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[CH3:50][S:51]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:29][CH2:28][N:27]2[C:23]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]=[C:15]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:24]=3[N:25]=[CH:26]2)[CH2:31][CH2:32]1)(=[O:53])=[O:52]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(Oc2nc3ccccc3c3c2ncn3CCC2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)N1CCC(CCn2cnc3c(Oc4ccccc4)nc4ccccc4c32)CC1
Reaction time: 1.5 h

Procedure:
To a solution of 1.00 g of 4-phenoxy-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinoline trifluoroacetate and 0.57 ml of triethylamine in 10 ml of methylene chloride, 0.16 ml of methanesulfonyl chloride was added dropwise at room temperature, and the mixture was stirred for 1.5 hours. The reaction mixture was added with water, and extracted with methylene chloride. The extract was washed with water, and dried, and then the solvent was evaporated to give a colorless liquid. The resulting colorless liquid was solidified with ethyl acetate, and the solid was washed with diethyl ether to give 0.80 g of colorless crystals. Recrystallization from a mixture of methylene chloride and ethyl acetate gave colorless crystals having the melting point of from 173.5 to 176° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3O)=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:51]=[N+:52]=[N-:53].CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C1COCC1>[N:51]([C@@H:23]1[CH2:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:22]1[NH:21][C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:7]([CH:18]2[CH2:19][CH2:20]2)[N:6]=1)=[N+:52]=[N-:53]
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of (1R,2S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (0.76 g, 1.7 mmol) in toluene (10 mL) and THF (10 mL) was added PPh3 (1.14 g, 4.57 mmol). The solution was cooled to 0° C. and HN3 (5.6 mL, 6.38 mmol) and a solution of diethylazodicarboxylate (0.69 mL, 4.37 mmol) in toluene (10 mL) were added. The reaction was stirred at rt overnight. The precipitates were removed by filtration and the filtrate was concentrated. Dissolve residue in 1 N HCl and EtOAc. Extract with EtOAc (3×30 mL). The aqueous phase was neutralized with sat. aq. NaHCO3 to pH 7.5 followed by a small amount of 6 N NaOH to pH 9. The aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 29–39% ethyl acetate/hexanes) to afford 0.8 g (78%) of N-[(1R,2R)-2-azido-2,3-dihydro-1H-inden-1-yl]-3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-amine as a solid: 1H NMR (CDCl3) δ 0.74–1.10, 1.63–1.71, 2.97–3.03, 3.36–3.42, 4.09–4.13, 4.26–4.29, 5.05, 5.57, 7.25–7.53; MS (ESI+) for C25H22Cl2N6 m/z 477 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].N1C=CC=CC=1.[CH3:13][O:14][C:15](Cl)=[O:16]>C(Cl)Cl>[C:15](=[O:16])([O:14][CH3:13])[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: COC(=O)Cl
Reactant: OCC(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)OCC(F)(F)F
Temperature: 25 °C

Procedure:
2,2,2-trifluoroethanol (105 g 1.05 mol), pyridine (87 g 1.1 mol) and 300 mL of methylene chloride were combined in a 1 L 3-neck round bottom flask. The flask was equipped with an overhead stirring mechanism, thermocouple, addition funnel, cold water condenser, and a dry nitrogen bubbler. The reaction flask was kept cool using a dry ice/acetone bath to keep the temperature in the range of −20° C. to −15° C. Methylchloroformate (100 g 1.05 mol) was added via an addition funnel at such a rate that the temperature was kept in the range of −20° C. to −15° C. Once the addition of the methylchloroformate was complete the reaction mix was allowed to warm to room temperature. The reaction mix was then quenched with 100 mL water. The methylene chloride solution was separated from the water and washed with 2×100 mL of 1N HCl. The methylene chloride was removed by distillation and the product was purified using fractional distillation on a concentric tube column (b.p.=90.0° C., purity=99.7%). The structure mass was confirmed by GC/MS.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]2[C:10]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:11][N:12]([C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: O=Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OCc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-Chloro-3-morpholino-1-trityl-1H-pyrazolo [4,3-c]pyridine-4-carbaldehyde (292.2 mg, 0.574 mmol) was dissolved in DCM (3 mL) and methanol (3 mL). Sodium borohydride (21.72 mg, 0.574 mmol) was then added and the reaction mixture was stirred at rt for 15 min. The reaction was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (5-40% EtOAc/Hexanes) gave (6-chloro-3-morpholino-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol. MS ESI calc'd. For C30H28ClN4O2 [M+H]+ 511. found 511.
Reaction SMILES: C[C:2]1[O:3][C:4](=O)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([N:13]2[CH:4]=[C:5]3[C:6]([CH:8]=[CH:9][CH:10]=[CH:11]3)=[N:7][C:2]2=[O:3])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: Cc1nc2ccccc2c(=O)o1
Product: O=c1nc2ccccc2cn1-c1ccccc1
Temperature: 160 °C
Yield: 35.2 %

Procedure:
A mixture of 2-methyl-4H-Benzo[d][1,3]oxazin-4-one (12; 1.0 g, 6.2 mmol) and aniline (13, R═H, 0.57 mL, 6.2 mmol, 1.0 eq) were heated at 160° C. (oil bath) for 12 hours. The reaction was cooled to room temperature and the resulting solid was recrystallized from EtOH to yield 485 mg (31%) of 14 as a yellow-orange crystalline solid: 1H NMR (CDCl3): 8.28 (d, 1H), 7.80-7.67 (m, 2H), 7.60-7.44 (m, 4H), 7.29-7.28 (m, 2H), 2.25 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1.[NH:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([C:22]3[C:23]([NH:28][C:29]4[C:30]5[CH:31]=[CH:32][N:33]=[C:34](Cl)[C:35]=5[CH:36]=[CH:37][C:38]=4[CH3:39])=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:16]2[CH:15]=[N:14]1.FC(F)(F)C(O)=O.CO>CC(O)C.CCN(CC)CC>[NH:13]1[C:17]2=[N:18][CH:19]=[N:20][C:21]([C:22]3[C:23]([NH:28][C:29]4[C:30]5[CH:31]=[CH:32][N:33]=[C:34]([NH:11][C:9]6[CH:8]=[CH:7][C:5]7[O:6][C:2]([F:1])([F:12])[O:3][C:4]=7[CH:10]=6)[C:35]=5[CH:36]=[CH:37][C:38]=4[CH3:39])=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:16]2[CH:15]=[N:14]1
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Reactant: Cc1ccc2c(Cl)nccc2c1Nc1ncccc1-c1ncnc2[nH]ncc12
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc2c(Nc3ccc4c(c3)OC(F)(F)O4)nccc2c1Nc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 150 °C

Procedure:
A mixture of 2,2-difluorobenzo[d][1,3]dioxol-5-amine (64 mg, 371 mop, N-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine (120 mg, 309 μmol) and 2,2,2-trifluoroacetic acid (95 μl, 1238 μmol) in i-PrOH (4 ml) was heated in a microwave reactor at 150° C. for 40 min. The mixture was poured into MeOH (10 ml) and Et3N (0.25 ml) was added. Solvent was removed under vacuum and the product was purified by flash chromatography eluting with MeOH/DCM (1-5%) to give N5-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-N1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-6-methylisoquinoline-1,5-diamine. MS Found: (ESI pos. ion) m/z 525 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:16])=[C:12]([CH:15]=1)[C:13]#[N:14].N1C=CC=CC=1.O>C(Cl)Cl>[Cl:16][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(N)ccc1Cl
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1ccc(Cl)c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A solution of ethyl chloroformate (3.68 g) in methylene chloride (5 ml) is added dropwise in about 20 minutes to a mixture of 5-amino-2-chlorobenzonitrile (5.2 g) and pyridine (2.77 g) in methylene chloride (75 ml), cooled to 0° C. and maintained in an inert atmosphere. At the end of the addition, the solution is stirred for 1 hour at 0° C. and is then brought to room temperature. At the end of the reaction, the mixture is poured into water (100 ml) and extracted with methylene chloride (2×80 ml); the organic phase is washed with water (2×80 ml), dried with sodium sulphate and concentrated under vacuum. 7.2 g of product are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:37]5[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Nc1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 120 °C
Yield: 37.9 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (268 mg, 1.2 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 335 (179.7 mg, yield: 38%). 1HNMR (DMSO-d6, 400 MHz): δ8.54 (s, 1H), 8.27 (s, 1H), 7.92-7.87 (m, 2H), 7.42 (t, J=0.8 Hz, 1H), 7.73-7.72 (m, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.43 (t, J=8.8 Hz, 1H), 7.17 (s, 1H), 6.54 (d, J=8.8 Hz, 1H), 6.28 (s, 1H), 4.26 (s, 2H), 3.11 (s, 2H). ESI-MS: m/z=475 [M+H+]
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[K+].Br[CH2:11][C:12]([OH:14])=[O:13]>O>[C:12]([CH2:11][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)([OH:14])=[O:13]
Reactant: O=C(O)CBr
Reactant: Sc1nnc(S)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CSc1nnc(S)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
In 200 ml of water were dissolved 15.0 g of 2,5-dimercapto-1,3,4-thiadiazole and 69 g of potassium hydroxide, and a solution of 13.9 g of bromoacetic acid in 30 ml of water was added thereto dropwise at room temperature. After the addition, the mixture was stirred at 60° C. for 1 hour, followed by allowing to cool to room temperature. The precipitated crystals were filtered and washed with water to obtain 18 g of the desired compound. Melting point: 161°-167° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH2:26][NH2:27])=[C:24]([CH2:28][CH3:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([S:37][C@@H:38]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:39](O)=[O:40])(=[O:36])[CH3:35].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.CN(C=O)C.C(Cl)CCl>>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH2:26][NH:27][C:39](=[O:40])[C@@H:38]([S:37][C:34](=[O:36])[CH3:35])[CH2:42][CH:43]([CH3:45])[CH3:44])=[C:24]([CH2:28][CH3:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(CC)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: CC(=O)S[C@@H](CC(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOc1nc(CC)c(CNC(=O)[C@H](CC(C)C)SC(C)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4′-(5-Aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (5.0 g, 11.0 mmol), (S)-2-acetylsulfanyl-4-methylpentanoic acid (dicyclohexylamine salt; 2.1 g, 11.0 mmol), 4-methylmorpholine (1.2 mL, 11.0 mmol), and 1-hydroxy-7-azabenzotriazole (1.5 g, 11.0 mmol) were combined and dissolved in DMF (120 mL, 1.6 mol) and then cooled at 0° C. for 10 minutes. EDC (2 mL, 11.0 mmol) was added and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The reaction was quenched with water (100 mL), the product extracted with EtOAc (100 mL), and then concentrated. The mixture was purified by column chromatography (0-50% EtOAc:hexanes) to obtain the acetylsulfanyl ester intermediate, 4′-{5-[((S)-2-acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:29][C:30]1[CH:31]=[CH:32][C:33]2[C:39](=O)[CH2:38][CH2:37][CH2:36][S:35][C:34]=2[CH:41]=1>C1COCC1>[Br:29][C:30]1[CH:31]=[CH:32][C:33]2[C:39](=[CH:2][O:3][CH3:4])[CH2:38][CH2:37][CH2:36][S:35][C:34]=2[CH:41]=1
Reactant: O=C1CCCSc2cc(Br)ccc21
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C1CCCSc2cc(Br)ccc21
Temperature: -75 °C
Reaction time: 1.25 h
Yield: 85.2 %

Procedure:
16.68 g (1.6 eq.) of (methoxymethyl)triphenylphosphonium chloride was suspended in 75 ml of abs. THF and deprotonated between −15° C. and −5° C. by adding via syringe 29.5 ml of 1.6 M n-butyllithium (hexane, 1.55 eq.). The resultant red ylide solution was cooled to −75° C. and treated with 7.82 g (30.4 mmol) of 8-bromo-3,4-dihydro-2H-benzo[b]thiepin-5-one, dissolved in 15 ml of abs. THF. The mixture was then kept for 0.3 h at −78° C. and for 1.25 h at room temperature. Pouring onto crushed ice, twofold extraction with diethylether, washing the organic phase with water, drying over magnesium sulfate, filtration and evaporation of the solvents yielded a crude product which was purified by flash chromatography (SiO2, hexane/ethylacetate 95/5); thereby, 7.39 g of 8-bromo-5-methoxymethylene-2,3,4,5-tetrahydrobenzo[b]thiepine was obtained as E/Z-mixture which was hydrolyzed as follows:
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].[CH3:24][O:25][CH:26]([O:37][CH3:38])[C:27]1[N:32]=[C:31]([O:33][CH3:34])[C:30]([CH2:35][OH:36])=[CH:29][CH:28]=1.O>CN(C)C=O>[Si:10]([O:36][CH2:35][C:30]1[C:31]([O:33][CH3:34])=[N:32][C:27]([CH:26]([O:37][CH3:38])[O:25][CH3:24])=[CH:28][CH:29]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1nc(C(OC)OC)ccc1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C(OC)OC)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.3 %

Procedure:
Imidazole (1.47 g) and t-butyldiphenylchlorosilane (3.54 g) was added to a solution of [6-(dimethoxymethyl)-2-methoxypyridin-3-yl]methanol (2.3 g) in N,N-dimethylformamide (23 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→10:1) to give 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(dimethoxymethyl)-2-methoxypyridine (5.47 g, 99%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2].Br[C:38]1[N:39]=[C:40]([NH:46][C:47]2[CH:48]=[C:49]3[C:54](=[CH:55][CH:56]=2)[CH2:53][N:52]([CH3:57])[CH2:51][CH2:50]3)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:38]2[N:39]=[C:40]([NH:46][C:47]3[CH:48]=[C:49]4[C:54](=[CH:55][CH:56]=3)[CH2:53][N:52]([CH3:57])[CH2:51][CH2:50]4)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:33][CH2:32][C:31]2[C:30]3[CH2:29][C:28]([CH3:35])([CH3:34])[CH2:27][C:26]=3[S:25][C:24]=2[C:23]1=[O:36])(=[O:3])[CH3:2]
Reactant: CN1CCc2cc(Nc3nc(Br)cn(C)c3=O)ccc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C)C4)n2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 53 %

Procedure:
A 25 mL sealed tube was charged with 247b (590 mg, 1.15 mmol), 5-bromo-1-methyl-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one 221b (400 mg, 1.15 mmol), CH3COONa (189 mg, 2.3 mmol), K3PO4 (611 mg, 2.3 mmol), PdCl2(dppf) (94 mg, 0.11 mmol) suspended in CH3CN (25 mL) and water (1 mL). The mixture was heated at 110° C. for 2 hours. The mixture was evaporated and the residue was purified by silical-gel column eluting with 20:1 methylene chloride/methanol to give 247c as a brown solid (400 mg, 53%). MS: (M+H)+ 656.