Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:23]([CH2:24][CH2:25][NH:26]C(=O)OCC)[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CC(O)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]3[N:23]([CH2:24][CH2:25][NH2:26])[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: NCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2cccnc21
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
A mixture of 20 parts of ethyl [2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]-pyridin-3-yl]ethyl]carbamate, 26.3 parts of potassium hydroxide and 200 parts of 2-propanol was stirred for 1.5 hour at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was evaporated again. The residue was taken up in a small amount of water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 2,2'-oxybispropane (+activated charcoal) and the whole was filtered over diatomaceous earth. The filtrate was allowed to crystallize. The crystallized product was filtered off (the filtrate was set aside) and dried, yielding a first fraction of 6.7 parts (40.6%) of 2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]pyridine-3-ethanamine. The filtrate, which was set aside (see above) was evaporated, yielding a second fraction of 6.6 parts (40.0%) of 2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]pyridine-3-ethanamine. Total yield: 13.3 parts (80.6%) of 2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]pyridine-3-ethanamine; mp. 101.7° C. (compound 187).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]1[C:16]2[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:22]>C1COCC1>[NH2:22][C:13]1[S:12][C:16]2[CH:17]=[C:18]([NH:21][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])[CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: Nc1ccc2nc(N)sc2c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: Nc1nc2ccc(NC(=S)NC(=O)c3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.3 %

Procedure:
Benzoylisothiocyanate (0.12 mL, 0.91 mmol) was added dropwise to a solution of benzothiazole-2,6-diamine (Example 1, 150 mg, 0.91 mmol) in 10 mL of THF at room temperature. The mixture was stirred at room temperature for 7 hours and then concentrated. The residue was washed with a 1:1 mixture of Et2O and hexanes. Yield: 97.3%, 1H-NMR (DMSO-d6): δ 12.65 (s, 1H); 11.55 (s, 1H); 8.00 (m, 3H); 7.60 (m, 5H); 7.38 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][CH3:14])=[O:12].[H-].[Na+].Br[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].[NH4+].[Cl-]>CN(C)C=O>[CH3:1][C:2]1[N:10]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(Br)c1ccccc1
Reactant: COC(=O)c1c(C)[nH]c2cnccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)n(C(C)c2ccccc2)c2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A mixture of methyl 2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (550 mg, 2.89 mmol) and sodium hydride (200 mg, 4.34 mmol) in N,N-dimethylformamide (3.0 mL) was stirred at room temperature for 0.5 hour, and then (1-bromoethyl)benzene (589 mg, 3.18 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated NH4Cl and extracted with ethyl acetate. Organic layers were combined and concentrated to give a residue. The residue was purified by chromatography (petroleum ether/ethyl acetate=5:1) to give methyl 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (800 mg, 94%).
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:36]([I:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C.O>[Cl:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:32](=[O:33])[C:31]3[CH:35]=[C:36]([I:40])[CH:37]=[C:38]([CH3:39])[C:30]=3[N:29]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1cc(I)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methanesulfonyl chloride (0.63 mL, 8.13 mmol) in acetonitrile (10 mL) was added dropwise a mixture of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Step D) (2.0 g, 7.75 mmol) and triethylamine (1.08 ml, 7.75 mmol) in acetonitrile (5 mL) at 0° C. The reaction mixture was then stirred for 15 minutes at 0° C. Then, 2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Example 1, Step A) (2.14 g, 7.75 mmol) was added, and stirring was continued for an additional 5 minutes. A solution of triethylamine (2.17 mL, 15.15 mmol) in acetonitrile (5 mL) was then added dropwise while keeping the temperature below 5° C. The reaction mixture was stirred 40 minutes at 0° C., and then methanesulfonyl chloride (0.63 mL, 8.13 mmol) was added. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were washed successively with 10% aqueous sodium bicarbonate (1×20 mL) and brine (1×20 mL), dried (MgSO4) and concentrated to afford 3.18 g of the title product as a crude yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>>[CH:13]1[C:14]2[CH:2]([NH:1][CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: ClCC1CO1
Product: OC(CCl)CNC1c2ccccc2-c2ccccc21

Procedure:
18.1 g of 9-aminofluorene are reacted with epichlorohydrin, following the procedure described in Example 47, to give 1-(9-fluorenylamino)-2-hydroxy-3-chloropropane, from which, without purification, (9-fluorenylaminomethyl)oxirane is obtained with methanolic sodium hydroxide solution, by the procedure described in Example 48. Reaction of this compound with 17.8 g of 4-trans-propenylguaethol gives 16.1g = 38.7% of theory of 1-(2-ethoxy-5-trans-propenyl-phenoxy)-2-hydroxy-3-(9-fluorenylamino)-propane, which crystallizes out from the reaction solution in the cold in the form of the free base. Colorless crystals which have a melting point of 119°-121° and are identical to the product described in Example 28.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[CH2:4][C@@H:5]([OH:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1>CO>[CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:32])[CH2:4][C@@H:5]([OH:16])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSCCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1
Solvent: CO
Product: CCCS(=O)CCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1

Procedure:
Oxidation of 4-[3-[ethyl[3-(propylthio)propyl]amino]-2(R)-hydroxypropoxy]benzonitrile with m-chloroperbenzoic acid was carried out as described for the stereoisomeric mixture in example 3. [α]D20 -18.6° (C 1.0, CH3OH).
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]([C@@:16]23[CH2:25][N:24]([S:26]([C:29]4[CH:30]=[N:31][C:32]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[CH:33][CH:34]=4)(=[O:28])=[O:27])[CH2:23][CH2:22][C:21]2=[CH:20][C:19]2[N:41]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[N:42]=[CH:43][C:18]=2[CH2:17]3)=[O:15])[CH2:9]1.Cl>O1CCCC1.O1CCOCC1>[OH:7][CH:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]([C@@:16]23[CH2:25][N:24]([S:26]([C:29]4[CH:30]=[N:31][C:32]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)=[CH:33][CH:34]=4)(=[O:27])=[O:28])[CH2:23][CH2:22][C:21]2=[CH:20][C:19]2[N:41]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[N:42]=[CH:43][C:18]=2[CH2:17]3)=[O:15])[CH2:9]1
Reactant: O=C(OCC1CC(OC2CCCCO2)C1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(OCC1CC(O)C1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid 3-(tetrahydropyran-2yloxy)-cyclobutylmethyl ester in tetrahydrofuran (0.6 mL) was treated with 4.0 M hydrogen chloride in dioxan (1.0 mL) for 30 minutes. The reaction mixture was evaporated under reduced pressure, the residue dissolved in dichloromethane and the solution washed with 2.0M sodium carbonate solution and brine. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC eluting with a mixture of acetonitrile and water containing 0.1% formic acid (2:3 to 85:15 by volume) to give the title compound as a white solid (0.007 g). 1H NMR (400 MHz, CHCl3-d): δ 8.52 (d, 1H), 7.77 (dd, 1H), 7.40-7.30 (m, 3H), 7.18-7.10 (m, 2H), 6.62 (d, 1H), 6.42 (d, 1H), 4.38-4.30 (m, 2H), 4.11 (dd, 2H), 3.80 (t, 5H), 3.66 (t, 4H), 3.27 (d, 1H), 2.88-2.80 (m, 1H), 2.58 (d, 1H), 2.48-2.34 (m, 4H), 2.18-2.06 (m, 4H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH3:11])[CH3:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19]CC)=[O:18])C>O>[CH2:1]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=2[CH3:11])[C:15](=[O:14])[C:16]([C:17]([OH:19])=[O:18])=[CH:22]1)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCNc1cccc(Cl)c1C
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)c(C)c21
Temperature: 110 °C
Yield: 70.2 %

Procedure:
Ten grams of N-ethyl-2-methyl-3-chloroaniline is allowed to react with 15 g of diethyl ethoxymethylenemalonate under heating at 110° C. for 30 minutes. Then, polyphosphoric acid (obtained from 50 g each of phosphoric acid and phosphorus pentaoxide) is added to be subjected to the reaction at 140° C. for 40 minutes. After the reaction, the mixture is poured into 600 g of water and ice, resulting in crystals separated out. The crystals are recovered by filtration, and a 10% sodium hydroxide solution is added to the fitrate and the mixture is refluxed for 1 hour. After refluxing, the mixture is treated with activated carbon and adjusted to pH 2 with concentrated hydrochloric acid, whereby there separate out light yellow crystals. Recrystallization from dimethylformamide yields 11 g of 1-ethyl-7-chloro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as the white, needle-like crystals. mp. 221°-222° C.
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].C(O)C.Cl.N[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>C(Cl)(Cl)Cl>[S:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:3]=[C:2]1[CH2:1][C:4]#[N:5]
Reactant: Nc1ccccc1S
Reactant: N#CCC#N
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N#CCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of malonodinitrile (13.22 g, 0.200 mole) in dry chloroform (100 mL) was added ethanol (9.2 g, 0.200 mole). Hydrogen chloride (8.0 g, 0.220 mole) was passed into the solution at room temperature and the resulting suspension was stirred for an additional 16 hours at room temperature. The excess of hydrogen chloride was removed by passing dry nitrogen into the reaction mixture. A solution of o-aminothiophenol (25 g, 0.200 mole) in chloroform was added to the reaction mixture dropwise during 30 min and the reaction mixture was stirred for 1 hour at 60° C. After that the reaction mixture was cooled to room temperature, washed with water (2×100 mL) and dried with magnesium sulfate. Chloroform was removed using a rotary evaporator. The solid residue was recrystallized from ethyl alcohol. White crystals. The yield was 26.1 g (75% of theory). Mp=101-103° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:61][C:58]1[S:59][C:60]2[C:52]([CH:47]3[CH2:48][O:49][CH2:50][CH2:51][O:46]3)=[CH:53][CH:54]=[C:55]([O:62][CH3:63])[C:56]=2[N:57]=1)=[O:8]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3cccc(N(C)C)c3)nc12

Procedure:
From 3-dimethylaminobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+18.7° (c=1.06, CHCl3), ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [F: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](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.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.[CH3:57][C:58]([NH2:62])([CH2:60][CH3:61])[CH3:59]>CN(C=O)C>[F: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]([NH:62][C:58]([CH2:60][CH3:61])([CH3:59])[CH3:57])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Reaction time: 16 h
Yield: 20.8 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.19 mmol), HATU (91.20 mmol, 0.24 mmol) and DIPEA (49 mg, 0.38 mmol) in 6 mL of DMF, 2-methylbutan-2-amine (21.60 mg, 0.24 mmol) was added in one portion at room temperature. Then the reaction mixture was stirred for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 15% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-tert-pentyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 20.7%) as a white solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.07 (s, 1H), 8.47-8.37 (m, 2H), 7.81 (s, 1H), 7.70 (dd, 1H, J=9.6, 2.1 Hz), 7.17 (t, 1H, J=2.1 Hz), 4.15 (s, 3H), 1.89 (q, 2H, J=7.6 Hz), 1.46 (s, 6H), 0.87 (t, 3H, J=7.5 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[Br:18][C:4]1[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
1.0 g (0.00255 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 25 ml of dioxane and treated with 2.1 ml of pyrrolidine. The mixture was stirred at room temperature for 4 hrs., the solvent was removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There was obtained 0.9 g (93%) of 4-(2-bromo-6-pyrrolidin-1-yl-pyridine-4-sulphonyl)- phenylamine as beige crystals; m.p.: 216° C. (dec).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:23])[CH:21]=[CH2:22])=[CH:14][CH:13]=2)[N:4]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH3:28][N:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:24])[F:25])=[N:4]2)=[CH:13][CH:14]=1)[C:20](=[O:23])[CH:21]=[CH2:22]
Reactant: C=CC(=O)NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(=O)N(C)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reaction time: 0.08 h
Yield: 26 %

Procedure:
A stirred solution of N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide (241 mg, 0.69 mmol) in dimethylformamide (5 ml) under argon was treated with sodium hydride (60% suspension in mineral oil, 28 mg, 0.7 mmol). The reaction mixture was stirred for 5 minutes then methyl iodide (0.05 ml) was added and the reaction mixture stirred for a further 1 hour. Reaction mixture was then quenched with 3 drops of water and 5 ml of 1M ammonia in methanol. Excess ammonia and methanol were removed by rotary evaporation. Reaction mixture was separated between ethyl acetate and brine. Organic layer was retained, dried over sodium sulphate and the solvent removed by rotary evaporation. Sample was purified by 5 g pre-pack silica column eluted with 50% ethyl acetate/petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a yellow oil (66 mg, 26%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][F:8])[S:5][CH:6]=1.[CH2:9]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]2[CH:22]=1)[CH2:10][C:11]#[CH:12]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]2[N:16]([CH:22]=[C:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]3[N:3]=[C:4]([CH2:7][F:8])[S:5][CH:6]=3)[N:14]=2)[CH:17]=1
Reactant: FCc1nc(Br)cs1
Reactant: C#CCCc1cn2cc(F)ccc2n1
Product: FCc1nc(C#CCCc2cn3cc(F)ccc3n2)cs1
Yield: 49.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 4-bromo-2-(fluoromethyl)thiazole (84 mg, 0.43 mmol) and 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (compound 223(E), 80 mg, 0.43 mmol). The crude residue was purified over C18 chromatography (prepacked 35 g silicagel column, H2O/CH3CN: from 100/0 to 80/20 as eluent) to afford 65 mg of 6-fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 47%) as a beige powder (Mp=82-84° C.).
Reaction SMILES: [CH2:1](C1C=C2C(COC2=O)=CC=1)[CH3:2].Br[C:14]1[C:15]([O:36][CH3:37])=[C:16]([C:22]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])(=[O:28])=[O:27])=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(B(CC)CC)C>>[CH2:1]([C:14]1[C:15]([O:36][CH3:37])=[C:16]([C:22]([CH2:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])(=[O:28])=[O:27])=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)OC2
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(Br)c1OC
Agent: CCB(CC)CC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(CC)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from ethyl 3-bromo-2-methoxy-6-(2-methylbenzenesulphonylmethyl)benzoate (Intermediate 62) and triethyl borane.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O1CCCC1.B>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(F)cc1Br
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of 2-bromo-4-fluorobenzoic acid (20 g, 91 mmol) in anhydrous THF (300 ml) at −10° C. was added dropwise borane tetrahydrofuran complex (1.0M soln in THF) (136.5 ml, 136.5 mmol). After complete addition the reaction was allowed to stir at room temperature for 4 hours. The reaction was quenched by the dropwise addition of water (20 ml). To the mixture was added saturated K2CO3 (200 ml) and water (300 ml). The organic layer was separated and the aqueous extracted with Et2O (2×300 ml). The combined organics were washed with water (2×500 ml), saturated NaCl (200 ml), dried over Na2SO4, filtered and evaporated to give the title compound (18 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:28])[N:4]([CH3:29])[C:3]1=[O:30])[CH2:12][CH2:11][CH:10]=[C:9]3[C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1.[H][H].C(OCC)C>C(OCC)(=O)C.[Pt]>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=4)=[C:6]2[C:5](=[O:28])[N:4]([CH3:29])[C:3]1=[O:30])[CH2:12][CH2:11][CH2:10][CH:9]3[C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3c2nc(C)cs2)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3c2nc(C)cs2)c1

Procedure:
1,3-Dimethyl-10-(4-methylthiazol-2-yl)-5-m-tolyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (Intermediate M) (100 mg, 0.24 mmol) was dissolved in ethyl acetate (20 mL) and the resulting solution was hydrogenated using the H-Cube® (10% platinum on carbon CatCart®), at atmospheric pressure of hydrogen and 20° C., for 6.5 hours. The solvent was removed under vacuum. The crude material was purified by chromatography on silica, eluting with 1-2% MeOH/DCM to obtain a gum. Diethyl ether was added and removed under vacuum to give the title compound as a solid.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>C1(C)C=CC=CC=1>[OH:26][CH2:25][CH:24]([NH:23][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH2:27][OH:28]
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)OC)s1
Reactant: NC(CO)CO
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC(CO)CO)s1
Yield: 55 %

Procedure:
To a stirred solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (100 mg, 0.31 mmol) in toluene (1.0 mL) was added 2-amino-1,3-propandiol (57 mg, 0.62 mmol) and TBD (13 mg, 0.09 mmol). After 15 h the reaction mixture was concentrated in vacuo then purified by chromatography (silica, 0 to 7.5% methanol in dichloromethane) to give the title compound (65 mg, 55%) as an off white oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:60][C:58]1[S:57][C:47]2[C:48]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=2[N:59]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 401 (M+H+, 100).