Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:2]([N:13]([CH:14]([CH3:19])[CH3:15])[CH3:11])[C:1]([OH:5])=[O:4])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: O=CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)N(C)C(C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 62 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with glyoxylic acid (618 mg, 6.72 mmol), toluene (20 mL), N,N-isopropylmethylamine (486 mg, 6.60 mmol) and 4-(tert-butoxycarbonylamino) phenylboronic acid (1.58 g, 6.66 mmol). The reaction was sealed with a plastic cap under a nitrogen atmosphere and stirred at room temperature for 7 d. After this time, the reaction was concentrated under reduced pressure. The resulting residue was subjected to flash chromatography to afford 25 in 62% yield (1.34 g) as a light brown solid: mp 320° C. dec, 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.42 (d, 2H, J=8.7 Hz), 7.37 (d, 2H, J=8.7 Hz), 4.23 (s, 1H), 3.28 (m, 1H), 3.17 (s, 1H), 2.23 (s, 3H), 1.47 (s, 9H), 1.15 (d, 3H, f=6.6 Hz), 1.11 (d, 3H, J=6.6 Hz); MS (ESI+) m/z 323 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19]Cl)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[C:30]([C:31]([F:34])([F:33])[F:32])=[N:29][N:28]=[C:27]1[SH:35].[I-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][S:35][C:27]3[N:26]([CH3:25])[C:30]([C:31]([F:33])([F:32])[F:34])=[N:29][N:28]=3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Reactant: Cn1c(S)nnc1C(F)(F)F
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(SCCCN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)nnc1C(F)(F)F

Procedure:
0.4 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (1.14 mmol), 0.22 g of 4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (1.2 mmol), 0.07 g of lithium-hydroxide (2.92 mmol) and a spatula tip of potassium iodide were stirred in 10 ml of dimethylformamide for 14 h at room temperature and for an additional 2 h at 80° C. After addition of water and ethyl acetate, the organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified twice by column chromatography on silica gel using dichloromethane-methanol (1-5%). Fractions containing the product were combined, the solvents evaporated, the residue stirred with acetonitrile yielding 0.03 g (5.3%) of the product as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH:18]([CH3:20])[CH3:19])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5]/[C:4](=[C:12]3/[C:13]([CH:18]([CH3:20])[CH3:19])=[N:14][NH:15][C:16]/3=[O:17])/[CH:3]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(S)cc1
Reactant: CC(C)C1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CC(C)C1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1

Procedure:
Example 20 was synthesized from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-isopropyl-1H-pyrazol-5(4H)-one and 4-aminothiophenol according to the procedure described in Example 19. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (bs, 6H) 3.33 (bs, 1H) 5.87 (s, 1H) 6.78 (d, J=8.34 Hz, 2H) 7.31 (d, J=8.34 Hz, 2H) 7.52 (bs, 1H) 7.77 (bs, 1H) 8.03 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'd for C21H20N4OS 376.47. found 377.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19].Cl>O1CCCC1.O1CCOCC1.O>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19])[CH2:9][CH3:10]
Reactant: CCCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-3-propylbenzene (16.6 g) in tetrahydrofuran (83 ml) cooled to −78° C. was added dropwise n-butyllithium (2.66M solution in n-hexane, 34 ml) over 9 minutes, and then the mixture was stirred for 1 hour. To this reaction solution was added dropwise N,N-dimethylformamide (7.7 ml) over 6 minutes, and the mixture was stirred for additional 20 minutes. To this reaction solution was added dropwise a 4M solution of hydrogen chloride in 1,4-dioxane (23 ml) over 5 minutes, and then the mixture was stirred after warming to room temperature. To this mixed solution was added water (83 ml), followed by a 6M aqueous solution of hydrochloric acid (12 ml), and then the mixture was extracted with n-hexane (80 ml). The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product of the titled compound (14.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH3:16])[C:13](=[O:24])[C:12]3[CH:25]=[C:26](I)[CH:27]=[CH:28][C:11]=3[NH:10][C:9]2=[O:30])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH3:16])[C:13](=[O:24])[C:12]3[CH:25]=[C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH3:31])[CH:27]=[CH:28][C:11]=3[NH:10][C:9]2=[O:30])=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2NC(=O)[C@@H]1c1ccc(Cl)cc1
Reactant: Cc1ccccc1B(O)O
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of (3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-1,4-benzodiazepine-2,5-dione (120 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol), 2-methylbenzene boronic acid (35 mg, 0.26 mmol) and sodium carbonate (220 μL, 2M in H2O) in ethanol (300 μL) and toluene (5 mL) was heated under argon, at 90° C., for 10 h. After the mixture was cooled at room temperature, the solvent was evaporated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (15 mL), dried (Na2SO4) and evaporated. Chromatography on silica (AcOEt/hexanes/CH2Cl2, 1:6:3) afforded the title compound (92 mg, 68%) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.78 (d, J=7.2 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 5.29 (s, 1H, CH), 6.51 (q, J=7.2 Hz, 1H, CH), 6.64–6.67 (m, 2H, ArH, 6.71 (d, J=8.4 Hz, 1H, ArH), 6.93 (d, J=8.4 Hz, 2H, ArH), 7.05–7.11 (m, 1H, ArH), 7.15 (dd, J=8.0 Hz, J=2.0 Hz, 1H, ArH), 7.20–7.26 (m, 3H, ArH), 7.35 (d, J=8.4 Hz, 2H, ArH), 7.56 (d, J=8.4 Hz, 2H, ArH), 7.61 (d, J=2.0 Hz, 1H, ArH), 7.91 (br s, 1H, NH). Mass spectrum (LCMS, ESI pos.): Calcd for C30H24Cl2N2O2: 514.0; found: 515.0 (M+H)+.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:53])[C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]5[N:33]=[CH:34][C:35]6[N:41]([CH3:42])[C:40](=[O:43])[C:39]([F:45])([F:44])[CH2:38][N:37]([CH:46]7[CH2:49][CH2:48][CH2:47]7)[C:36]=6[N:50]=5)=[C:27]([O:51][CH3:52])[CH:26]=4)[CH2:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[NH2:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]3[N:33]=[CH:34][C:35]4[N:41]([CH3:42])[C:40](=[O:43])[C:39]([F:45])([F:44])[CH2:38][N:37]([CH:46]5[CH2:49][CH2:48][CH2:47]5)[C:36]=4[N:50]=3)=[C:27]([O:51][CH3:52])[CH:26]=2)=[O:53])[CH2:22][CH2:23]1
Reactant: COc1cc(C(=O)N2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(N)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A mixture of 0.150 g (0.20 mmole) of {1-[4-(9-Cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoyl]-piperidin-4-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester, 1 mL of piperidine and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.025 g of 2-[4-(4-amino-piperidine-1-carbonyl)-2-methoxy-phenylamino]-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-6).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.[C:32]([O:36]C)(=[O:35])[CH2:33]O.C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[C:29]([C:26]1[NH:25][C:24]([C:22]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([C:14]3([O:20][CH2:33][C:32]([OH:36])=[O:35])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:8]=2[C:5]2[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=2)=[O:23])=[N:28][CH:27]=1)#[N:30]
Reactant: COC(=O)CO
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3(OCC(=O)O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (48.0 mg, 0.114 mmol)(prepared in Example 1, step (h)) in 1 mL of DCM was added methyl glycolate (0.215 mL, 2.78 mmol), TFA (0.036 mL, 0.464 mmol), and the mixture was stirred for 8 h at RT. The mixture was concentrated and the methyl ester of the title compound was eluted from a 10-g SPE column with 50% EtOAc/hexanes. The resulting ester was dissolved in 1 mL of MeOH, 2N KOH (0.30 mL, 0.60 mmol) was added and the mixture stirred for 8 h at RT. The title compound was purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-60% CH3CN in 0.1% TFA/H2O over 12 min to give 13 mg (30%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.34 (d, J=8.6 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 5.79 (m, 1H), 4.03-3.94 (m, 2H), 3.88-3.80 (m, 2H), 3.72 (s, 2H), 2.35-2.27 (m, 2H), 2.13-2.06 (m, 4H), 1.60 (t, J=6.3 Hz, 2H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O5, 477.2 (M−H). found 477.2.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].[S]>N1C=CC=CC=1.[Cl-].[Na+].O>[NH:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:18]=[C:1]1[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1ccccc1N
Reactant: Cc1nc2ccccc2s1
Agent: [Cl-]
Agent: [Na+]
Agent: [S]
Solvent: O
Solvent: c1ccncc1
Product: c1ccc2[nH]c(-c3nc4ccccc4s3)nc2c1
Yield: 13.7 %

Procedure:
The heterogeneous mixture consisting of methylbenzothiazole (59.6 g, 0.4 mol), ortho-phenylenediamine (43.2 g, 0.4 mol) and sulfur (38.4 g, 1.2 mol) in 300 ml of pyridine was heated at the reflux point of pyridine for 22 hours. The reaction mixture was cooled and poured into a solution of brine. After extraction with ethyl acetate, washing of the organic phase 3 times with water, drying over sodium sulfate and concentration of the solvent under vacuum, the solid obtained was washed with acetone. After drying, 2-(1H-benzimidazol-2-yl)benzothiazole (13.8 g, yield: 13%) was obtained in the form of a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([CH:11]([NH:19]S(C(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:9]=[CH:10][C:2]1=2.Cl.O1CCOCC1>CO>[NH2:19][CH:11]([C:7]1[C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=[CH:9][CH:8]=1)[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1cccc2c1OCCO2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCC(N)c1cccc2c1OCCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (160 mg; 0.43 mmol) in MeOH (2 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.22 ml; 0.88 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pentanoate as a yellow solid. LC-MS (conditions A): tR=0.47 min.; [M+H]+: 266.11 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:28][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, p-hydroxybenzaldehyde (99.6 g), n-octadecylamine (200.0 g) and p-toluenesulfonic acid (13.4 g) were added to toluene (1200 ml) and the mixture was refluxed with heating and simultaneously the azeotropic water was removed. After about 2 hours, the reaction mixture was cooled to room temperature to precipitate a crystal, which was filtered off under reduced pressure. This crystal was recrystallized from isopropanol to obtain the desired product (207.9 g). Yield 75%; m.p. 101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a stirred solution of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (350 mg, 1.06 mmol) from Step 3 of this Example in DCM (15 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (287 mg, 1.17 mmol), and the mixture was allowed to warm to rt and stirred for a further 2 h. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford a solid. The solid was triturated with Et2O, filtered, then dried to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (336 mg, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.41 (br s, 1H), 8.22 (s, 1H), 8.04-8.15 (m, 2H), 7.63 (d, J=8.3 Hz, 1H), 5.70 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][CH3:11])=[CH:14][C:15]=2[N+:20]([O-:22])=[O:21])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-methoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.13 (s, 1H), 9.01 (d, J=2.7, 1H), 8.83 (d, J=9.3, 1H), 8.24-8.20 (m, 1H), 7.76 (d, J=2.7, 1H), 7.52 (d, J=8.7, 1H), 7.35-7.31 (m, 1H), 3.90 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:12][O:11][CH:10]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: COCCBr
Reactant: C1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(C)N1CCCCCC1
Yield: 72 %

Procedure:
1-Methoxyethylazepane was obtained using procedure 1a, from azepane (10.7 g, 0.107 mol) in methanol (50 cm3), 1-bromo-2-methoxyethane (15.0 g, 0.107 mol) and potassium carbonate (15.0 g). After distillation in vacuo (42-44° C., 1.0 mmHg), 1-methoxyethylazepane was obtained as a colourless liquid in ca. 72% yield. δH (500.13 MHz, CDCl3) 3.6 (6H, m), 3.38 (3H, s), 2.68 (2H, t), 1.59 (8H, br m). ESI-MS: m/z=158 [M+H]+ (100). Calcd. for C9H19NO: 158.1545; found: 158.1535.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:5]=1[CH2:6][O:7][C:8]1[C:9]2[N:10]([C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:11]=[CH:12][C:13]=1[F:14].Cl>C1COCC1.C(O)C>[F:3][C:4]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:5]=1[CH2:6][O:7][C:8]1[C:9]2[N:10]([C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)c(F)ccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc2c(OCc3c(F)cccc3F)c(F)ccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.14 ml (1.14 mmol) of 1 N lithium hydroxide solution were added to 365 mg (0.76 mmol; purity about 76%) of ethyl 8-[(2,6-difluorobenzyl)oxy]-7-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylate Example 269A in 16.6 ml of THF/ethanol (5/1), and the mixture was stirred at RT overnight. Another 2.67 ml (2.67 mmol) of 1 N lithium hydroxide solution were added and the mixture was stirred at RT overnight. Under reduced pressure, the reaction mixture was freed from organic solvent, and the aqueous phase was acidified to pH 4 with 6 N hydrochloric acid whilst cooling with ice water. The solid formed was filtered off and dried under high vacuum. This gave 236 mg of the target compound (87% of theory, purity 94%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[C:7]([C:20](OCC)=[O:21])=[CH:6]2.CC(C)(C)C([O:31][CH2:32][C:33]1[S:34][C:35]2[C:40]([N:41]=1)=[CH:39][C:38]([NH2:42])=[CH:37][N:36]=2)=O.C[Al](C)C>C1(C)C=CC=CC=1.Cl>[OH:31][CH2:32][C:33]1[S:34][C:35]2[C:40]([N:41]=1)=[CH:39][C:38]([NH:42][C:20]([C:7]1[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[C:9]3[C:5]([CH:6]=1)=[CH:4][C:3]([C:2]([F:1])([F:26])[F:25])=[CH:11][CH:10]=3)=[O:21])=[CH:37][N:36]=2
Reactant: CC(C)(C)C(=O)OCc1nc2cc(N)cnc2s1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(C)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(Cn2c(C(=O)Nc3cnc4sc(CO)nc4c3)cc3cc(C(F)(F)F)ccc32)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 39.8 %

Procedure:
To a solution of 150 mg (0.415 mmol) of ethyl 5-trifluoromethyl-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylate prepared according to the protocol described in the preceding step and 132 mg (0.498 mmol) of (6-amino-thiazolo[5,4-b]pyrid-2-yl)methyl 2,2-dimethylpropanoate, obtained in step 4.2, in 1.5 mL of dry toluene, maintained under an inert atmosphere, is added dropwise, at 0° C., 0.31 mL (0.623 mmol) of a trimethylaluminium solution (2M/toluene). The reaction mixture is stirred at 110° C. for 15 hours and then concentrated to dryness. The crude reaction product is then diluted with normal hydrochloric acid solution. The product is extracted with ethyl acetate and then purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate, to give 82 mg of the expected product.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:31])[O:12][C@H:13]([C:15](=[O:30])[NH:16][C@@H:17]2[C:23](=[O:24])[NH:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[O:19][C@@H:18]2[CH3:29])[CH3:14])=CC=1)([O-])=O.[F:32][C:33]([F:40])([C:36]([F:39])([F:38])[F:37])[CH2:34][NH2:35]>>[CH3:29][C@@H:18]1[C@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:31])[NH:35][CH2:34][C:33]([F:40])([F:32])[C:36]([F:39])([F:38])[F:37])[CH3:14])=[O:30])[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19]1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1C
Reactant: NCC(F)(F)C(F)(F)F
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 60 mg (0.14 mmol) of carbonic acid (S)-1-((6R,7S)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl ester 4-nitro-phenyl ester and 0.304 ml (2.8 mmol) of 2,2,3,3,3-pentafluoropropylamine was stirred at room temperature overnight. The mixture was purified by flash-chromatography on silica gel using an ascending gradient of ethyl acetate in heptane as the eluent to yield 60 mg (98% of theory) of the title compound as a white solid, MS m/e (%): 440.3 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[S:23][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=2)[S:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCn1nc(Cl)ccc1=O
Reactant: Cc1csc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1csc(-c2ccc(=O)n(CCNC(=O)OC(C)(C)C)n2)c1
Temperature: 90 °C

Procedure:
A suspension of tert-butyl 2-(3-chloro-6-oxopyridazin-1(6H)-yl)ethylcarbamate (2000 mg, 7.31 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (535 mg, 0.731 mmol), and 4-methylthiophen-2-ylboronic acid (2075 mg, 14.6 mmol) in DME (1.6 mL) with Na2CO3 (10.9 mL, 21.9 mmol) [2M] was sparged with argon for 1 min, then heated to 90° C. for 2 h. The mixture was partitioned between CH2Cl2 and 5% NaHCO3, and the organic layer was dried over MgSO4 and dried onto dry silica. The product was purified on 80 g silica eluting with 1>2.5% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 336 Calc'd exact mass for C16H21N3O3S: 335. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.40 (s, 9 H) 2.28 (s, 3 H) 3.61 (d, J=5.02 Hz, 2 H) 4.32 (t, J=5.27 Hz, 2 H) 5.11 (br. s., 1 H) 6.91-6.99 (m, 2 H) 7.20 (s, 1 H) 7.55 (d, J=10.04 Hz, 1 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 13.71, 26.35, 37.78, 49.41, 77.33, 121.32, 125.75, 127.40, 127.95, 136.53, 139.01, 153.88, 157.97.