Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[N:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:14][C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@H:24]4[CH2:29][CH2:28][C@H:27]([CH2:30][C:31]([O:33]C)=[O:32])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[O:16])=[N:12][N:11]=2)=[N:5][CH:4]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCOC(C)=O>O.C1COCC1.CO>[N:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:14][C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C@H:24]4[CH2:25][CH2:26][C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][CH2:29]4)=[CH:20][CH:19]=3)=[O:16])=[N:12][N:11]=2)=[N:5][CH:4]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccncn4)o3)cc2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccncn4)o3)cc2)CC1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
A solution of lithium hydroxide (101 mg, 2.41 mmol) in H2O (1.5 mL) was added in one portion to a solution of methyl {trans-4-[4-({[5-(pyrimidin-4-ylamino)-1,3,4-oxadiazol-2-yl]-carbonyl}amino)phenyl]cyclohexyl}acetate (Example 416, 105 mg, 0.24 mmol) in a mixture of THF (1.8 mL) and MeOH (3 mL) and the reaction mixture was stirred at 35° C. for 2 h. Citric acid (50 mL) and EtOAc (50 mL) were added and the layers were separated and the aqueous layer was filtered to leave a solid. The solid was washed with water (10 mL) to give the title compound as a yellow brown solid (60 mg, 59%); 1H NMR δ 1.07-1.18 (2H, m), 1.41-1.51 (2H, m), 1.69-1.85 (5H, m), 2.14-2.16 (2H, d), 7.24 (2H, d), 7.71 (2H, d), 7.92 (1H, d), 8.69 (1H, d), 8.87 (1H, s), 11.00 (1H, s), 12.06 (2H, s); MS m/e MH+ 423.
Reaction SMILES: [C:1]1([C@H:7]2[O:12][CH2:11][C@H:10](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O-:27])(=[S:26])[CH3:25].[K+].C1(C)C=CC=CC=1>CN(C)C(=O)C>[C:24]([S:26][C@H:10]1[CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:12][CH2:11]1)(=[O:27])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H](c3ccccc3)OC2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)S[C@H]1CO[C@@H](c2ccccc2)OC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
A mixture of 30 g (90 mmol) of trans-2-phenyl-5-(p-toluenesulfonyloxy)-1,3-dioxane (prepared as described in Tetrahedron, 48, 5941-5950), 15.3 g (134 mmol) of potassium thioacetate, 240 ml of toluene and 60 ml of N,N-dimethylacetamide was stirred at 100° C. for 3 hours and then at 110-120° C. for 7 hours. After cooling, the reaction mixture was partitioned between toluene and water. The organic layer was then washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oily residue was purified by chromatography on a silica gel (200 g) column using a 1:4 mixture of ethyl acetate and hexane as the eluant to afford the crude title compound as a solid. This solid was recrystallized from a mixture of ethyl acetate and hexane to afford 10 g (yield 47%) of the title compound as brown needle-like crystals.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][C@@H:10]1[C@H:20]1[O:24]C(C)(C)[N:22]([C:27](=[O:29])[CH3:28])[C@H:21]1[CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([F:38])[CH:34]=1)[CH2:30][C@H:21]([NH:22][C:27](=[O:29])[CH3:28])[C@H:20]([OH:24])[C@H:10]1[CH2:11][C@@H:12]([O:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:13][NH:9]1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCCC(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](OCCC(C)C)CN1
Reaction time: 2 h
Yield: 100 %

Procedure:
Add 4M hydrogen chloride in dioxane (8 mL) to (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(3-methyl-butoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.079 g, 0.15 mmol). Stir 2 hours and evaporate to give the title compound as a foam (0.089 g, 100%).
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10](O)[CH2:11][CH3:12].[BrH:15]>C1CCCCC1>[Br:15][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:14]
Reactant: Br
Reactant: CCC(O)CCCCCCCCCO
Solvent: C1CCCCC1
Product: OCCCCCCCCCCCCBr
Yield: 73 %

Procedure:
1,10-Dodecanediol (2 g) was dissolved in 25 ml of cyclohexane, and 57% hydrobromic acid solution (25 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:ethyl acetate=7:3) gave 12-bromododecan-1-ol as white crystals at a 73% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:9]=2[NH:8][C:7]1=[O:19])=[O:5])[CH3:2].[CH2:20](I)[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:9]=2[N:8]([CH2:20][CH3:21])[C:7]1=[O:19])=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C1CCc2ccc(OC)cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C1CCc2ccc(OC)cc2N(CC)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.4 %

Procedure:
A suspension of 3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (0.45 g, 1.71 mmol), ethyl iodide (0.41 mL, 5.1 mmol) and Cs2CO3 (1.672 g, 5.1 mmol) in acetonitrile (5 mL) was stirred at room temperature for 6 hrs. The reaction mixture was filtered and the solid was washed with acetonitrile. The combined filtrate and washer were evaporated under reduced pressure. The crude product was purified by flash chromatography on a short silica gel column using EtOAc/hexane (3:7) as an eluent. The title compound (0.241 g, 48%) was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][N:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16]([C:23]2[S:24][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[N:15]1>>[CH3:13][N:14]1[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][C:16]([C:23]2[S:24][C:25]([S:28]([NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=3)(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[N:15]1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cn1nc(-c2ccc(S(=O)(=O)Cl)s2)cc1C(F)(F)F
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(-c3cc(C(F)(F)F)n(C)n3)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]-thiophene-5-sulfonyl chloride as described in the synthetic METHOD B giving a yellow solid with a purity of 93%. MS (electrospray, [M+H]+) m/z 481.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[OH-].[K+].Cl>CO>[Br:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cc2nc(-c3ccccc3)cn2cc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.7 %

Procedure:
A 50 mL round bottomed flask was charged with methyl 6-bromo-2-phenylimidazo[1,2-a]pyridine-7-carboxylate (400 mg, 1.21 mmol) and suspended in methanol (12.1 mL). To that stirring solution was added 3.0M potassium hydroxide (0.805 mL, 2.42 mmol). The flask was fitted with a reflux condenser and placed in an oil bath preheated to 70° C. After 2.5 hours, LCMS showed clean and complete conversion of the starting material to a major peak with the desired mass (m/z=318 [M+H]+). The mixture was cooled to room temperature and 1.0N HCl was added. The reaction mixture was cooled in an ice bath and a pink solid formed. After 30 minutes, the solids were filtered and dried under high vacuum overnight. 6-Bromo-2-phenylimidazo[1,2-a]pyridine-7-carboxylic acid (283 mg, 0.892 mmol, 73.9% yield) was recovered as a pink solid. 1H NMR (400 MHz, DMSO-d6) ppm 9.04 (1H, s), 8.51 (1H, s), 8.09 (1H, s), 7.96-8.03 (2H, m), 7.45-7.54 (2H, m), 7.35-7.43 (1H, m) Mass found 318 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:14]=2[Cl:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Na].[CH:40](/[S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41]\[CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][C:14]=2[Cl:25])[C:6]=1/[CH:7]=[CH:8]/[C:9]([NH:48][S:45](/[CH:40]=[CH:41]/[CH2:42][CH2:43][CH3:44])(=[O:47])=[O:46])=[O:11]
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2/C=C/C(=O)O)c(Cl)c1
Reactant: CCC/C=C/S(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCC/C=C/S(=O)(=O)NC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(OCCCCC)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
(E)-3-(4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methylimidazol-5-yl)-2-propenic acid (150 mg) was dissolved in N,N-dimethylformamide (1.5 ml) and carbonyldiimidazole was added. The mixture was stirred at room temperature for 3 hr. To the reaction mixture was added (E)-1-penten-1-ylsulfonamide sodium salt (97 mg), and the mixture was stirred at room temperature for 3 hr and left standing for one day. The reaction mixture was diluted with water (1.5 ml) and adjusted to pH 4 with 1N hydrochloric acid under ice-cooling. The precipitated powder was collected by filtration and washed with water. The resulting white powder was suspended in ethanol (0.75 ml) and heated. The mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with ethanol and dissolved in N,N-dimethylformamide (0.75 ml) at 80° C. Water (0.25 ml) was added at the same temperature and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed with N,N-dimethylformamide—water (1:1) and then with water to give (E)-3-(4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methylimidazol-5-yl)-N-((E)-1-penten-1-ylsulfonyl)-2-propenamide (160 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[N:15]([CH3:19])[C:16](=O)[NH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>>[Cl:22][C:16]1[N:15]([CH3:19])[C:14]2[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:1][CH3:2])=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: CCc1ccccc1-c1cccc2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccccc1-c1cccc2nc(Cl)n(C)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
A mixture of 190 mg (0.753 mmol) of 7-(2-ethylphenyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 1.5 mL of phosphorus oxychloride was stirred at 80° C. for 5 hours. After cooling, the reaction mixture was poured into ice and neutralized by 12 N sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 3-10% ethylacetate/n-hexane gradient mixture to give 123 mg (60%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]2)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[BrH:23]>O>[BrH:23].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Agent: Br
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CCNCC1
Yield: 81 %

Procedure:
A mixture of 84 parts of ethyl 4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinecarboxylate and 750 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 4 hours. The precipitated product is filtered off, washed with water and petroleum-ether, and dried, yielding 71 parts (81%) of N-(4-chloro-2-nitrophenyl)-4-piperidinamine hydrobromide; mp. 275° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:34])[CH3:33])=[CH:3][CH:4]=1)#[N:20]
Reactant: CC(=O)Cl
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1c(C#Cc2ccc(NC(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (95 mg, 0.29 mmol), prepared as described in Example 1H, is dissolved in THF (1.4 mL). Triethylamine (84 μL, 0.6 mmol) is added, followed by dropwise addition of acetyl chloride (44 μL, 0.5 mmol). This is stirred at room temperature for 1 h. The reaction mixture is partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide (103 mg, 96%) as a yellow solid.
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=CC=1.[N+:39]([C:42]1[CH:54]=[CH:53][C:45]([CH2:46][O:47][C:48]([NH:50][CH:51]=N)=[O:49])=[CH:44][CH:43]=1)([O-:41])=[O:40].FC(F)(F)S([O-])(=O)=O>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([N:30]2[CH2:36][CH2:35][CH2:34][N:33]([CH:51]=[N:50][C:48]([O:47][CH2:46][C:45]3[CH:53]=[CH:54][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=3)=[O:49])[CH2:32][CH2:31]2)=[O:29])[CH2:11]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=C(N=CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Following a procedure similar to that described in Preparation 4, but using 2.10 g of (2S,4S)-4-(4-methoxy-benzylthio)-2-(1-homopiperazinylcarbonyl)-1-(4-nitro-benzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in Preparation 2(i)] and 0.93 g of N-(4-nitrobenzyloxycarbonyl)formamidine, 2.38 g of the trifluoromethanesulfonate of the title compound were obtained. The salt was treated by the same procedure as described in Preparation 4(ii), to give 1.90 g of the title compound.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[C:19]([N:4]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:1][N:2]=[N:3]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cc1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a stirred suspension of 0.969 g of ethyl (1H-tetrazol-5-yl)acetate in 9mL of tetrahydrofuran were added successively 0.932 mL of triethylamine and 1.68 g of trityl chloride at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and 1 mol/L hydrochloric acid, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 1.23 g of ethyl (1-trityl-1H-tetrazol-5-yl)acetate.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]#[N:19])=[CH:12][CH:11]=3)#[N:4].[CH2:20](Br)[CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[CH2:20]([N:9]1[C:10]2[CH:11]=[CH:12][C:13]([C:18]#[N:19])=[CH:14][C:15]=2[C:16]2[C:8]1=[CH:7][CH:6]=[C:5]([C:3]#[N:4])[CH:17]=2)[CH2:21][CH2:22][CH3:23]
Reactant: N#Cc1ccc2[nH]c3ccc(C#N)cc3c2c1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c2ccc(C#N)cc2c2cc(C#N)ccc21
Temperature: 110 °C
Yield: 81.3 %

Procedure:
A slurry of sodium hydride (50% in oil, 480 mg) in 50 ml of anhydrous dimethylformamide is treated with 3,6-dicyanocarbazole (2.17 g) and heated at 110° C for two hours. The reaction mixture is then treated dropwise with butylbromide (1.37 g) and heated for about 16 hours at 110° C. The reaction mixture is poured into water and the resultant precipitate collected by filtration. The solid is dissolved in dichloromethane and filtered through 200 ml of silica gel to yield 2.22 g of the title compound, melting point 215°-217°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].Br[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2cccnc2)cc1OC(C)c1ccccc1Cl

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.0 Eq.), 3-bromopyridine (69 mg, 0.44 mmol, 1.2 Eq.) and Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.55 mL, 1.10 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as am off-white solid (58 mg, 0.16 mmol, 42%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.93 (3H, s), 5.87 (1H, q), 6.93 (1H, s), 7.25-7.41 (4H, m), 7.68 (1H, dd), 7.72 (1H, dd), 8.58 (1H, dd), 8.78 (1H, d).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:47])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:48]([NH:51][C:52]1[S:53][C:54]([S:58](Cl)(=[O:60])=[O:59])=[C:55]([CH3:57])[N:56]=1)(=[O:50])[CH3:49]>>[CH3:2][O:3][C:4](=[O:47])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:45][CH3:46])=[CH:42][CH:43]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[S:58]([C:54]1[S:53][C:52]([NH:51][C:48](=[O:50])[CH3:49])=[N:56][C:55]=1[CH3:57])(=[O:59])=[O:60])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CCOc1ccc([C@H]2COc3cc4c(cc3O2)CNC(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)OC)C4)cc1
Agent: Cl
Product: CCOc1ccc([C@H]2COc3cc4c(cc3O2)CN(S(=O)(=O)c2sc(NC(C)=O)nc2C)C(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)OC)C4)cc1
Yield: 73.9 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-(4-ethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester hydrochloride (18 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (11 mg) according to General Procedure E to give (S)-2-{[(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-(4-ethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (17 mg). This was hydrolyzed according to General Procedures N and B to give the title compound (5 mg). LCMS: (m/z) 783.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@H:33]([CH3:42])[C:34]([N:36]1[CH2:39][C:38]([F:41])([F:40])[CH2:37]1)=[O:35].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:41][C:38]1([F:40])[CH2:39][N:36]([C:34](=[O:35])[C@H:33]([NH:32][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=2)=[O:23])[CH3:42])[CH2:37]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@@H](N)C(=O)N1CC(F)(F)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.4 %

Procedure:
A round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.24 mmol), (R)-2-amino-1-(3,3-difluoro-azetidin-1-yl)-propan-1-one (98 mg, 0.60 mmol), HOBT (41 mg, 0.27 mmol) and EDC (51 mg, 0.27 mmol). DMF (1.1 ml) was added followed by N,N-diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-50% EtOAc) to afford 89 mg (61%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow solid.