Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O:34][CH2:35][C:36](O)=[O:37])(C)(C)C.N=C=N>C(Cl)Cl>[OH:37][CH2:36][C:35]([N:27]1[CH2:28][CH2:29][N:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:15][CH:16]=[N:17]3)=[CH:22][CH:21]=2)[CH2:25][CH2:26]1)=[O:34]
Reactant: CC(C)(C)OCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCNCC4)ccc23)CC1
Agent: N=C=N
Solvent: ClCCl
Product: O=C(CO)N1CCN(c2ccc3c(C4CCNCC4)ncnc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(7-Piperazin-1-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 45, was added to a mixture of t-butoxyacetic acid (0.15 mmol) and PS-carbodiimide (0.2 mmol) in anhydrous DCM (2 mL). The mixture was shaken at rt overnight. It was then filtered and the resin washed with DCM. The combined filtrate and washings were concentrated in vacuo. To this was then added 3M HCl/MeOH (2 mL) and stirred at rt for 2 h and then concentrated in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:30])=[C:24]([F:35])[CH:23]=1)#[N:2].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:38])[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:30])=[C:24]([F:35])[CH:23]=1)#[N:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OCC1CCNCC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4)c3cc2C#N)CC1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
After suspending 320 mg of N-(4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)-2-fluorophenyl)-N′-cyclopropylurea in 20 ml of tetrahydrofuran, there were added 1 ml of formaldehyde (37% aqueous solution), 80 mg of acetic acid and 280 mg of sodium triacetoxyborohydride while stirring at room temperature. After stirring for 20 minutes, a 2N aqueous sodium hydroxide solution and ethyl acetate were added for extraction. The extract was passed through a glass filter coated with NH type silica gel, and the silica gel was thoroughly washed with an ethyl acetate:methanol=20:1 mixed solvent. The organic solvents were combined and distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered to obtain 130 mg of a light yellow solid.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:41][CH2:42][NH:43][S:44]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=1)(=[O:46])=[O:45])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:15]1[CH2:41][CH2:42][NH:43][S:44]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=1)(=[O:46])=[O:45])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Methyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino} ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (step 13, 1.0 eq) was dissolved in THF:MeOH (1:1) (0.1M), then added 1N NaOH. The mixture was kept stirred overnight at room temperature. The solvent was stripped off and the residue was dissolved in water to form a basic solution, which was neutralized with diluted HCl solution to precipitate the product. The solid was collected by filtration, washed with water, rinsed with hexane, then dried to give the desired product in 86% yield. HRMS calc for [C41H37Cl3N2O6S2+H] 823.12314 found 823.12292.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:29](=[O:30])[CH2:28][N:27]([CH3:31])[C:26]1=[O:32])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:29](=[O:30])[CH2:28][N:27]([CH3:31])[C:26]1=[O:32])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.3 %

Procedure:
A solution of 0.133 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-N-(3-methyl-2,5-dioxo-1-imidazolidinyl)valeramide in 5 ml of methanol was treated with 0.014 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2.5 hours at room temperature and then evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether and hexane to give 0.049 g of (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-N-(3-methyl-2,5-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](Cl)=[O:26].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([C:25]([N:3]2[CH2:4][CH2:5][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[NH:13][C:14]=3[C:2]2([CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:26])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC1(c2ccccc2)NCCc2c1[nH]c1ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(c2ccccc2)c2[nH]c3ccccc3c2CCN1C(=O)c1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 21.7 %

Procedure:
The title compound was prepared by the addition of 1-methyl-1-phenyl-1,3,4,9-tetrahydrobeta-carboline (105 mg, 400 μmol), CHCl3 (9 mL), 3,4-difluorobenzoyl chloride (85 mg, 480 μmol), and DIEA (140 μL, 800 μmol) to a 25 mL flask. The solution was allowed to stir at 60° C. under N2 for 17 hours. The reaction solution was concentrated, and the crude sample was chromatographed (SiO2, 100% hexane to 20% EtOAc) to yield 35 mg of title compound; 1H NMR (CDCl3) δ 7.54 (1H, d), 7.48 (2H, d), 7.12-7.32 (9H, m), 4.05 (1H, m), 3.64-3.70 (1H, m), 3.19 (1H, m), 2.96 (1H, m), 2.29 (3H, s); MS (ESI): 403 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:19]([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.O>[CH3:20][N:19]([CH3:21])[C:16]([CH:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)=[O:18]
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of 1-(4-nitrophenyl)piperidine-4-carboxylic acid, (CH3)2NH (2.37 g, 29.06 mmol), HATU (11.05 g, 29.06 mmol) and DIPEA (7.51 g, 58.12 mmol) in 30 mL of THF, was stirred at room temperature overnight. The mixture was added to 20 mL of water, extracted with EA, washed with water and brine, dried over Na2SO4. The volatiles were removed in vacuo to give 4.2 g of N,N-dimethyl-1-(4-nitrophenyl)piperidine-4-carboxamide. MS (m/z)=278 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:13][C:12]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:11]=3[NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:29]1[CH:33]=[C:32]([CH:34]=[O:35])[N:31]=[CH:30]1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[S:15]([OH:35])(=[O:17])(=[O:16])[CH3:18].[NH:29]1[CH:33]=[C:32]([CH2:34][N:10]2[C:11]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:12]=3[CH2:13][N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[C@H:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9]2)[N:31]=[CH:30]1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)O
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 170.1 %

Procedure:
Charge (R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile (30 g, 1 eq.) and imidazole-4-carboxaldehyde (7.8 g, 1.1 eq.) into 300 mL of CH2Cl2. Cool the mixture to 0-5° C., add trifluoroacetic acid (30 mL, 5 eq.), and follow with trifluoroacetic acid anhydride (15 mL, 1.5 eq.). Stir the solution at 0-5° C. for 15 min, then add a slurry of Na(OAc)3BH (21 g, 1.3 eq.) in 50 mL of CH2Cl2 while keeping the temperature below 20° C. Remove the ice-bath and stir the mixture at room temperature for 18 h. Cool the mixture to 0-5° C., adjust pH with 10% NaOH to 12.5 (ca. 250 mL used). Stir at room temperature for 30 min. Split the phases, and extract the aqueous phase with 50 mL of CH2Cl2. Wash the combined organic layer with 100 mL of water. Swap the CH2Cl2 to 300 mL of EtOH by distillation at normal pressure. Cool the solution to 20-25° C. over 1 h and stir for 30 min. Filter the slurry and wash the wet cake with 50 mL of EtOH. Transfer the wet cake to a 500-mL 3-neck flask, and add 300 mL of EtOH. Heat to reflux for 10 minutes. Slowly add methanesulfonic acid (4.8 mL). Keep stirring the clear solution at reflux for 30 min. Cool the mixture to room temperature over 1 h and stir at room temperature for 1 h. A slurry forms at 65° C. Filter the slurry and wash the cake with 50 mL of EtOH. Dry the cake at 40° C. in a vacuum oven overnight. The product is obtained as white solid (36.5 g, 84% yield).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].S(Cl)(Cl)=O.[NH2:28][C:29]1[CH:30]=[N:31][C:32]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[O:43])=[CH:38][CH:37]=2)=[N:33][CH:34]=1>ClCCl.C1COCC1>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=2)=[CH:17][C:13]=1[C:14]([NH:28][C:29]1[CH:34]=[N:33][C:32]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[O:43])=[CH:38][CH:37]=2)=[N:31][CH:30]=1)=[O:15]
Reactant: CN1CCN(C(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccc(C(F)(F)F)c5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
A mixture of intermediate 1 (Example 2) (40 mg, 1.2 mmol) and thionyl chloride (875 μL, 12 mmol) in dichloromethane (20 mL) was heated under reflux for 6 h. The reaction mixture was evaporated to dryness. To the residue was added (4-(5-aminopyrimidin-2-ylamino)phenyl)(4-methylpiperazin-1-yl)methanone (20 mg, 0.064 mmol) and TEA (44 μL, 0.31 mmol) in THF (7 mL). The reaction mixture was stirred at room temperature for 1 h and evaporated. The residue was purified by HPLC to give title compound as a yellow solid (21 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]2)[O:12]1.C(=O)([O-])[O-].[K+].[K+].[CH:40](I)([CH3:42])[CH3:41]>C(#N)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH:40]([CH3:42])[CH3:41])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]2)[O:12]1
Reactant: CCOC(=O)CCC1CC(NC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCC1CC(N(C[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C(C)C)C1
Temperature: 90 °C
Reaction time: 17.5 h
Yield: 15 %

Procedure:
A solution of the above crude ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate in acetonitrile (30 mL) was treated with potassium carbonate (6.3 g, 46 mmol) and isopropyl iodide (3.9 mL, 39 mmol). The reaction mixture in a sealed tube was heated at 90° C. for 6.5 h; HPLC indicated a 4:1 mixture of product to starting material. The reaction mixture was stirred overnight (17.5 h) at rt, treated with additional isopropyl iodide (2.0 mL, 20 mmol), and heated at 90° C. for 3 h; HPLC/LC MS indicated nearly complete conversion. The reaction mixture was cooled to rt and the solids were removed by vacuum filtration, rinsing with CH3CN, and the filtrate was concentrated in vacuo to afford a dull orange oil with precipitate. Purification by column chromatography (5×14.5 cm silica; 0-10% 7 N methanolic NH3/CH2Cl2) afforded the title compound (0.49 g, 15%) as a white foam/colorless oil. The mixed fractions containing product were repurified by column chromatography (4×10.5 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) to afford the title compound (1.66 g, 40%) as a white foam/colorless oil contaminated with the bisreductive amination byproduct from Step 1: MS (ESI+) for C25H38N6O5 m/z 503.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:40]=[CH:39][C:23]([CH2:24][C@H:25]2[CH2:29]OS(=O)(=O)[N:26]2C(OC(C)(C)C)=O)=[CH:22][CH:21]=1.O>CN(C=O)C>[NH2:26][C@@H:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([Cl:19])=[CH:40][CH:39]=1)[CH2:29][NH:18][C:16]1[CH:15]=[N:14][N:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:3]=[N:4][CH:5]=[CH:6]3)[CH:17]=1
Reactant: Nc1cnn(-c2ccc3cnccc3c2)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Cl)cc2)COS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H](CNc1cnn(-c2ccc3cnccc3c2)c1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (9.6 mg, 251 μmol) was added to a mixture of 1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (44 mg, 209 μmol) and (S)-tert-butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (109 mg, 314 μmol) in DMF (1 mL) at ambient temperature and the mixture was stirred at ambient temperature for 1.5 hours. H2O (15 mL) was added, and the mixture was extracted with DCM (4×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in DCM (3 mL), TFA (2 mL) was added, and the mixture was stirred at ambient temperature for 2 hours. Toluene (3 mL) was added, and the mixture was concentrated under reduced pressure. The resulting orange oil was dissolved in DCM, evaporated onto a silica gel plug, and purified by flash chromatography (Biotage Si 25+M, 5% to 10% 2 N NH3 in MeOH/DCM) to provide N-((S)-2-amino-3-(4-chlorophenyl)propyl)-1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (18 mg, 23% yield) as an off-white solid. LCMS (API-ES) m/z (%): 412.2 (100%, M++H); 1H NMR (300 MHz, CDCl3) δ ppm 1.54 (br s, 3H), 2.62 (dd, J=13.1, 8.1 Hz, 1H), 2.79-2.94 (m, 2H), 3.15 (dd, J=11.8, 2.6 Hz, 1H), 3.25 (d, J=4.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H) 7.45 (s, 2H), 7.64 (d, J=5.5 Hz, 1H), 7.89 (s, 1H), 8.00 (s, 2H), 8.51 (d, J=5.5 Hz, 1H), 9.20 (s, 1H). (S)-tert-Butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was prepared in a similar manner as that described for (S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide in Scheme 1, using (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-011434)) instead of (S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:17]([CH3:19])[CH3:18])[C:13](=[O:16])[NH:14][N:15]=2)=[C:4]([Cl:20])[CH:3]=1.N([O-])=O.[Na+].[C:25]([CH2:27][C:28]([NH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:29])#[N:26].[N:36]1C=CC=CC=1>O.Cl>[CH2:34]([O:33][C:31](=[O:32])[NH:30][C:28](=[O:29])[C:27]([C:25]#[N:26])=[N:36][NH:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:17]([CH3:18])[CH3:19])[C:13](=[O:16])[NH:14][N:15]=2)=[C:6]([Cl:8])[CH:7]=1)[CH3:35]
Reactant: c1ccncc1
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: CC(C)c1cc(Sc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Sc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A mixture of 6-(4-amino-2,6-dichloro-phenylsulfanyl)-4-isopropyl-2H-pyridazin-3-one (85) (3.40 g, 10.4 mmol) in water (135 mL) and concentrated hydrochloric acid (68 mL) cooled to 0° C. was treated with a solution of sodium nitrite (853 mg, 12.36 mmol) in water (7.0 mL) via Pasteur pipette under the surface of the reaction mixture. This was followed by a water rinse (1.0 mL) of the Pasteur pipette. The resulting yellow mixture was stirred at 0° C. for 30 min. More concentrated hydrochloric acid (7.0 mL) was added. The reaction was stirred at 0° C. for an additional 1.3 h. The solids were removed by filtration through filter paper and were rinsed with water. The clear, yellow diazonium salt solution of the filtrate was quickly poured into a solution of cyanoacetylurethane (1.77 g, 11.33 mmol), pyridine (75 mL) and water (204 mL) cooled to 0° C. Upon mixing, orange-red solids immediately formed. This mixture was stirred at 0° C. for 1 h. At this time, the solids were collected by filtration through filter paper. The solids were washed with water, air-dried under house vacuum for 2 h, and then dried under vacuum to afford (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (86) (2.98 g, 58%) as an orange solid; ES(+)-HRMS m/e calcd for C19H18Cl2N6O4S (M+H)+ 497.0560, found 497.0559. Exact Mass=496.0487; Molecular weight=497.36
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49]C(=O)OC(C)(C)C)[CH2:44]2)=[C:27]2[CH:33]=[CH:32][N:31](S(C3C=CC=CC=3)(=O)=O)[C:28]2=[N:29][CH:30]=1)=[O:23])=O)(C)(C)C.C1COCC1>CO.[OH-].[Na+].CCOC(C)=O>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH2:49])[CH2:44]2)=[C:27]2[CH:33]=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2[nH]ccc2c1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.4 %

Procedure:
To solution of tert-butyl {(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (194.4 mg, 0.2400 mmol) in MeOH (2.0 mL), aq. NaOH (1.0 M, 2.0 mL) was added followed by THF (2.0 mL). After stirring at room temperature for 5 h, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added. The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (46.6 mg, 41%). LCMS calc. for C22H22F2N7OS (M+H)+: m/z=470.1. found 470.2. 1H NMR (500 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.49 (s, 1H), 9.04 (s, 1H), 7.64-7.47 (m, 3H), 7.35 (d, J=3.3 Hz, 1H), 7.27 (t, J=8.8 Hz, 2H), 6.57 (d, J=3.4 Hz, 1H), 3.29-3.23 (m, 1H), 3.10-3.03 (m, 1H), 3.00-2.86 (m, 2H), 2.85-2.77 (m, 1H), 1.87-1.79 (m, 1H), 1.79-1.65 (m, 2H), 1.24-1.10 (m, 1H) ppm.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.[Cl:11][CH2:12][C:13]#[C:14][CH2:15]Cl>C(O)C>[Cl:11][CH2:12][C:13]#[C:14][CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCC#CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ClCC#CCOc1ccccc1
Temperature: 30 °C
Yield: 53.8 %

Procedure:
A mixture of phenol (50.8 g), potassium hydroxide (30 g), ethanol (200 ml) and water (50 ml) was stirred and heated under reflux for 1 hour, then cooled to 30° C. A solution of 1,4-dichlorobut-2-yne (100 g) in ethanol (60 ml) was added dropwise over 3.5 hours, then the mixture was stirred at ambient temperature for 18 hours and filtered. The filter cake was washed with ethanol (60 ml), and the filtrate and washings were combined. The solvents were removed in vacuo, and the residue was distilled to give 1-chloro-4-phenoxybut-2-yne as a colourless oil (52.5 g), b.p. 92°-98° C. at 0.53 mbar.