Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([Cl:19])[CH:13]=1.Cl[C:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[C:22]=1[Cl:31]>C1COCC1.Cl.C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:21]2[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[C:22]=2[Cl:31])=[C:14]([Cl:19])[CH:13]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
LiHMDS (1.0 M solution in hexanes, 53.0 mL, 53.0 mmol) was added dropwise to a stirred solution of 4-bromo-2-chlorophenylamine (7.10 g, 35.0 mmol) in THF (15 mL) cooled to −78° C. After one hour, 4,5,6-trichloronicotinic acid (3.73 g, 16.5 mmol) was added dropwise as a solution in THF (12 mL). The reaction was allowed to warm to room temperature slowly while stirring overnight. The suspension was diluted with 1 M HCl and ethyl acetate, and the aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over Na2SO4 and concentrated to a tan solid. The solid was triturated with diethyl ether overnight and the solids were isolated by filtration to provide the desired product (25) as a tan-colored solid (4.85 g, 75%). MS APCI (−) m/z 395, 397 (M-, Cl, Br pattern) detected.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:13]([NH:17][C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH:39]([F:41])[F:40])[CH:36]=4)[NH:31][N:30]=3)[N:27]=2)[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([NH:17][C:18]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[C:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH:39]([F:40])[F:41])[CH:36]=4)[N:31]([CH2:2][C:3]([NH:5][CH3:6])=[O:4])[N:30]=3)[N:27]=2)[N:22]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:21]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CNC(=O)CCl
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 2-chloro-N-methylacetamide (80 mg, 744 μmol) in DMF (28.0 mL) under Ar, potassium carbonate (280 mg, 2.03 mmol) was added at 25° C. After 1 h, N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (70 mg, 132 μmol) in DMF (7.00 mL) was added and the reaction was stirred at 70° C. After 6 h, the reaction was cooled to 25° C. and quenched with water (350 mL). The product was extracted with ethyl acetate (2×250 mL). The organic layer was dried over sodium sulfate, filtered through Celite, and the solvent removed in vacuo to give a beige solid. The solid was triturated in hexanes (20 mL), filtered and dried in vacuo (200 mTorr, 25° C.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(methylamino)-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62.2 mg, 103 μmol, 78%) as a light brown solid. MS (M)'=602; 1H NMR (DMSO-d6) δ: 9.10 (s, 1H), 8.60 (s, 1H), 8.22 (m, 2H), 7.88 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.41 (dd, J=2.3, 9.0 Hz, 1H), 7.21 (t, J=74.5 Hz, 1H), 5.73 (s, 2H), 5.27 (s 2H), 3.58 (t, J=8.0 Hz, 2H), 2.65 (d, J=4.5 Hz, 3H), 1.51 (s, 9H), 0.86 (t, J=7.8 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[ClH:4].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:24]([N:26]1[CH2:34][CH2:33][CH2:32][C@H:27]1[C:28](OC)=[O:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[ClH:4].[CH2:1]([NH:3][C:28](=[O:29])[C@@H:27]1[CH2:32][CH2:33][CH2:34][N:26]1[C:24](=[O:25])[C@H:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:22])[NH2:23])[NH:15][C:13]([O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])[CH3:2]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Reactant: CCN
Agent: Cl
Solvent: CO
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1

Procedure:
To a cold solution of 9.7 g. ethylamine in 50 ml. of methanol is added 2 g. of Nα -benzyloxycarbonyl-L-arginyl-L-proline, methyl ester, hydrochloride. The reaction is let stand in a sealed pressure bottle at room temperature and then warmed occasionally to 40°-45° C. during eight days. It is then evaporated to small volume under reduced pressure. The residual solution is dropped into stirred ethyl ether to precipitate a somewhat sticky white solid which is dried under reduced pressure; [α]D25 -53° (c 1.02, methanol); ultraviolet in methanol λmax 257 E11 4.2.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:9]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]2=[N:7][CH:8]=1)[NH2:2].[CH:26](=O)[CH3:27]>C(Cl)Cl.CN(C=O)C.[Cu](Cl)Cl>[CH3:26][C:27]1[N:4]2[C:5]3[CH:11]=[C:10]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[N:9]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=3[N:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: CC=O
Reactant: Cn1cc(-c2cc3nc(NN)cnc3n2COCC[Si](C)(C)C)cn1
Agent: Cl[Cu]Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc2cnc3c(cc(-c4cnn(C)c4)n3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.5 %

Procedure:
To a flask was added 2-hydrazinyl-6-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.100 g, 0.278 mmol, Preparation #P.2.1) and acetaldehyde (0.079 mL, 1.3 mmol) in DCM (3 mL). The mixture was stirred at rt for about 90 min. The mixture was concentrated in vacuo to give a residue. The residue was transferred to a flask and copper(II) chloride (0.075 g, 0.56 mmol) in DMF (3 mL) was added. The mixture was heated to about 90° C. for about 2 h. The mixture was cooled to rt, diluted with ice water (50 mL) and the solid was collected by filtration. The solid was taken up in DCM/MeOH and the insoluble solids were collected by filtration while the mother liquor was purified by flash chromatography (25 g silica gel column, DCM/EtOAc/MeOH 1:0:0 to 0:1:0 to 9:0:1) to give a solid. The solids were combined to give 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.04 g, 37%): LC/MS (Table 2, Method c) Rt=1.48 min; MS m/z 384 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:8][S:9]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:11])=[O:10]
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At r.t. to a solution of tetrahydro-4H-pyran-4-ol (90 uL, 1 mmol; Aldrich, Cat. No. 198234) in methylene chloride (3 mL) was added methanesulfonyl chloride (91 uL, 1.2 mmol), followed by triethylamine (0.20 mL, 1.5 mmol) and 4-dimethylaminopyridine (12 mg, 0.098 mmol). The mixture was stirred at r.t. for 3 h. It was diluted with methylene chloride. The solution was washed with water and brine, dried over Na2SO4. After filtration, the filtrate was concentrated to yield 0.21 g of the product (crude) which was directly used in the next step reaction without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])(=[O:15])=[O:14])[CH:6]=[C:5]([CH2:25][OH:26])[N:4]=1.Br[CH:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:26][CH2:25][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])(=[O:14])=[O:15])[CH2:35][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: CCOC(=O)CC(C)Br
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCOc1cc(CO)nc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(CCOc1cc(CO)nc(CO)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 20 h

Procedure:
To a solution of 767 mg of N-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-2-nitro-benzenesulfonamide in 15 ml of DMF, under argon, was added 344 μl of ethyl 3-bromo-butyrate and 1.38 g of K2CO3. The mixture was stirred for about 20 hours at 40° C. and then filtered through a sinter of porosity 4. The cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (Merck SuperVarioPrep 90 g column, Si60 15-40 μm), using a gradient of 0 to 10% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 395 mg of ethyl 4-[[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-(2-nitro-benzenesulfonyl)-amino]-butanoate were obtained. LC/MS (B): tr=2.72 min; [M+H]+: m/z 498; [M+HCO2H−H]−: m/z 542.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18]2)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].CO.[OH-].[Na+].Cl>C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][C:4]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18]2)([CH2:3][C:1]#[N:2])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(=O)O)c(Nc3ccccc3)n2)CC1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-(cyanomethyl)-4-[4-(methoxycarbonyl)-3-(phenylamino)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.12 g, 0.27 mmol) in THF (1.8 mL) was added MeOH (1 mL), and 1M aqueous NaOH (0.82 mL, 0.82 mmol). The mixture was heated to 50° C. for 2 hours. The mixture was then cooled to ambient temperature and acidified to pH 3-4 with 1N aqueous HCl. The mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].[O:10]1[CH2:31][CH:11]1[CH2:12][O:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:16]([CH3:30])([CH3:29])[CH2:15]1>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:31][CH:11]([OH:10])[CH2:12][O:13][CH:14]2[CH2:15][C:16]([CH3:30])([CH3:29])[N:17]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18]([CH3:21])([CH3:20])[CH2:19]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CC1(C)CC(OCC2CO2)CC(C)(C)N1OC1CCCCC1
Reactant: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OCC(O)COC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)cc1

Procedure:
4-Vinylphenol is reacted with 4-(2,3-epoxypropoxy)-1-cyclohexyloxy-2,2,6,6-tetra-methylpiperidine (=epoxide A5) analogously to Example B6) to form the title product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>>[F:19][C:13]([F:18])([C:14]([F:15])([F:16])[F:17])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cn1

Procedure:
In a manner analogous to that described in example 30a), the alkylation of the 5-hydroxy-pyridine-2-carboxylic acid methyl ester with potassium carbonate and trifluoro-methanesulphonic acid 2,2,3,3,3-pentafluoropropyl ester yielded the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester as a light yellow oil. MS (ISP): m/z=285 [M]+. b) In a manner analogous to that described in example 30b), the hydrolysis of the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester with lithium hydroxide yielded the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid as a white solid. MS (ISP): m/z=271 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.C(O[C:13](CC)([CH2:38]C)[C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=2)=[C:16]([CH:35]([CH3:37])[CH3:36])[CH:15]=1)(=O)CC([O-])=O.[C:42]([OH:45])(=[O:44])C>O>[CH:20]([C:18]1[CH:19]=[C:14]([CH:13]([CH3:38])[C:42]([OH:45])=[O:44])[CH:15]=[C:16]([CH:35]([CH3:36])[CH3:37])[C:17]=1[O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=1)([CH3:21])[CH3:22]
Reactant: CCC(CC)(OC(=O)CC(=O)[O-])c1cc(C(C)C)c(Oc2ccc([N+](=O)[O-])c(OC)c2)c(C(C)C)c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(Oc2c(C(C)C)cc(C(C)C(=O)O)cc2C(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
Sulphuric acid (1.0 mL, 20%) was added to a mixture of diethyl(3,5-diisopropyl-4-[3-methoxy-4-nitrophenoxy]benzyl) malonate (1.4 g), acetic acid (5 mL) and water (5 mL). After heating for 8 hours at 80° C., the reaction mixture was concentrated and ethyl acetate was added to the residue. The organic phase was washed with water and brine. After recrystallization (ethyl acetate/petrolium ether), 1.1 g of 3,5-diisopropyl-4-(3-methoxy-4-nitrophenoxy)phenylpropionic acid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:20]=1[C:21](OC)=[O:22]>C1C=CC=CC=1.ClCCl>[CH3:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21](=[O:22])[N:1]([C:2]1[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1)[CH2:29]2
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Reactant: COC(=O)c1c(C)cccc1CBr
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc2ccc(N3Cc4cccc(C)c4C3=O)cc21
Yield: 64 %

Procedure:
Ethyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate B) (7.66 mmol, 1 equiv.) was dissolved in benzene (30 ml), and methyl 2-(bromo-methyl)-6-methylbenzoate (8.42 mol, 1.1 equiv.) and TEA (9.19 mmol, 1.2 equiv.) were added at 25° C. and the mixture was refluxed for 12 h. The reaction mixture was reduced under reduced pressure and the residue was taken up in dichloromethane (30 ml), washed with water and sat. NaCl solution (5 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in hexane). Yield: 64%
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:39]([N:43]=[C:44]=[O:45])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][C:44]([NH:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH:5]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(C)(C)N=C=O
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (55 mg, 0.11 mmol) in dry DCM (0.5 mL) was added triethylamine (0.015 mL, 0.11 mmol), followed by tert-butyl isocyanate (0.013 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 1.5 h. LCMS showed mainly required product with 6% SM. The reaction mixture was diluted with DCM and methanol and then concentrated in vacuo. The resultant residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was evaporated in vacuo to give the title compound (52 mg, 84%). LCMS (System A) RT=1.15 min, ES+ve m/z 562/564 (M+H)+.
Reaction SMILES: C([O:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([Cl:21])[C:19]([Cl:20])=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[C:11]3[N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:7]1=[O:27])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:21][C:18]1[C:19]([Cl:20])=[C:12]2[C:11]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:10][CH:9]=[C:8]3[C:13]2=[C:14]([CH:17]=1)[C:15](=[O:16])[N:6]([OH:5])[C:7]3=[O:27]
Reactant: CC(C)(C)ON1C(=O)c2ccc(N3CCCC3)c3c(Cl)c(Cl)cc(c23)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccc(N3CCCC3)c3c(Cl)c(Cl)cc(c23)C(=O)N1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A mixture of 2-tert-butyloxy-5,6-dichloro-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (50.0 mg, 0.12 mmol, from Example M3-B) and TFA (1.0 mL) was stirred at room temperature for 2 hours and poured into ice water. The solid was washed with water and ether, and dried to give 26 mg of the title compound, mp 200-201° C.
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>C(O)C>[C:9]([C:6]([C:7]#[N:8])=[C:3]([S:4][CH3:5])[NH:21][CH2:20][CH2:19][S:18][CH2:17][C:16]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:11])#[N:10]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Product: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Bis(methylthio)methylenemalononitrile [prepared according to the procedure described in Chem. Ber., 95, 2861 (1962)] (9.94 g, 58.4 mmole) was added with stirring to a solution of 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine (10.0 g, 58.4 mmole) in 100 ml of absolute ethanol. After stirring at room temperature for 90 minutes, the solvent was removed by evaporation under reduced pressure, and the residue placed on silica gel and chromatographed to yield the title compound (15.65 g).
Reaction SMILES: Br[CH:2]([C:9](=O)[CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[S:25])[NH2:24])=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:25][C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([CH3:10])[N:24]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(Br)C(C)=O
Reactant: NC(=S)c1ccc(OCCCCl)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1sc(-c2ccc(OCCCCl)cc2)nc1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of ethyl 3-bromo-4-oxopentanoate (2 g, 8.98 mmol, 1 eq), and 4-(3-chloropropoxy)benzenecarbothioamide ax71 (2.06 g, 8.97 mmol, 1 eq) in dimethylformamide (4 ml) is stirred at 100° C. for 2 h. The reaction mixture is then added to ethyl acetate (200 ml) and the precipitate filtered off. The organic layer is washed with water (4×100 ml), brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. Purification by chromatography over silicagel (eluent: benzine/ethyl acetate 95:5 to 85:15) affords 1.3 g of ethyl {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetate i102.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:10][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=4[C:7]#[N:8])=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(Br)cc4C#N)ncnc32)CC1
Temperature: 160 °C
Yield: 9 %

Procedure:
A mixture of 5-bromo-2-hydroxy-benzonitrile (Oakwood Products, Inc., West Columbia, S.C., USA; 18 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-bromo-2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (4 mg, 30%) as a white solid. Mass spectrum MH+=499.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].Cl.O1CCOC[CH2:18]1>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:13])([F:14])[F:15]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
A mixture of 4-amino-3-(trifluoromethoxy)benzoic acid (8.88 g 40.2 mmol), MeOH (142 mL) and hydrochloric acid in 1,4-dioxane (4.0 M, 142 mL, 568 mmol) was stirred at room temperature for 72 h. After removal of the organic solvent the pH of the residue was adjusted to pH 8 and the aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried and concentrated under vacuum to afford the title compound (9.3 g, 39.6 mmol, 95% yield). MS (ESI) m/z 236.1 [M+1]+.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][C@H:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15]
Reactant: C[C@H](CI)Cn1c(=O)ccc2ccccc21
Reactant: CCCOC1CCNCC1
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)Cn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
A 4 mL vial was charged with crude (S)-1-(3-iodo-2-methylpropyl)-1H-quinolin-2-one (0.190 g), 4-propyloxypiperidine (0.137 g, 0.96 mmol) and dry CH3CN (2.5 mL). The mixture was shaken at 50° C. for 24 h and then purified by cation-exchange CC followed by flash CC (SiO2; EtOAc/MeOH 1:4) to give the title compound (0.051 g, 17%). 1H NMR (CD3OD) δ 7.85 (d, J=9.6 Hz), 7.70-7.63 (m, 2H), 7.60 (brt, J=7.8 Hz, 1H), 7.26 (brt, 7.6 Hz), 6.63 (d, J=9.6 Hz, 1H), 4.39-4.23 (m, 2H), 3.37 (t, J=6.6 Hz), 3.28-3.18 (m, 1H), 2.77-2.69 (m, 1H), 2.64-2.58 (m, 1H), 2.35 (dd, J=8.4, 12.0 Hz), 2.51-2.21 (m, 1H), 2.18 (dd, J=4.8, 12.0 Hz), 2.13-2.04 (m, 1H), 2.00-1.92 (m, 1H), 1.84-1.75 (m, 2H), 1.58-1.32 (m, 4H), 0.95-0.85 (m, 6H); 13C NMR (CD3OD) δ 163.7, 140.2, 139.5, 130.8, 129.2, 12.5, 121.4, 120.4, 115.2, 75.3, 69.5, 63.6, 52.3, 51.5, 46.8, 31.4, 31.3, 30.0, 23.1, 16.1, 9.8.