Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@@H:5]2[C@@H:7]([CH2:23][N:24]([CH3:49])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[N:33](OCC[Si](C)(C)C)[C:32]4[CH:41]=[C:42]([C:45]([F:48])([F:47])[F:46])[CH:43]=[CH:44][C:31]=4[N:30]=3)[CH2:8][C@@H:9]([N:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH:20]5[CH2:22][CH2:21]5)[C:13]=4[CH:12]=[CH:11]3)[C@@H:4]2[O:3]1.[ClH:51]>CO>[ClH:51].[ClH:51].[ClH:51].[CH:20]1([NH:19][C:18]2[C:13]3[CH:12]=[CH:11][N:10]([C@@H:9]4[CH2:8][C@H:7]([CH2:23][N:24]([CH3:49])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]5[NH:33][C:32]6[CH:41]=[C:42]([C:45]([F:48])([F:47])[F:46])[CH:43]=[CH:44][C:31]=6[N:30]=5)[C@@H:5]([OH:6])[C@H:4]4[OH:3])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:21][CH2:22]1
Reactant: CN(CCCCc1nc2ccc(C(F)(F)F)cc2n1OCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CN(CCCCc1nc2ccc(C(F)(F)F)cc2[nH]1)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 34.5 %

Procedure:
7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-{[methyl({4-[6-(trifluoromethyl)-1-[2-(trimethylsilyl)ethoxy]-1H-1,3-benzodiazol-2-yl]butyl})amino]methyl}-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (103.7 mg, 0.14 mmol) in conc. HCl solution (2 ml, 21.54 mmol) and methanol (2 ml) was heated to 40° C. for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between sat. NaHCO3(aq) (10 ml) and EtOAc (10 ml). A small amount of MeOH (−1 ml) was added to aid dissolution, and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 ml), the combined organics were then dried (MgSO4) and concentrated to afford 32.2 mg (40.5%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](B2OC(C)(C)C(C)(C)O2)=[N:18]1>>[NH:17]1[C:25]2[C:20](=[C:21]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: COCCNc1nc(Cl)nc2c1cnn2C
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: COCCNc1nc(-c2cccc3[nH]ncc23)nc2c1cnn2C

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-methoxy-ethyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 130. NMR: (CDCl3): 3.48 (s, 3H, CH3), 3.77 (t, H, ArH, J=5.13 Hz), 4.04 (m, 2H, CH2), 4.18 (s, 3H, CH3), 5.80 (sbr, H, NH), 7.53 (t, H, ArH, J=7.29 Hz), 7.63 (d, H, ArH, J=8.29 HZ), 7.95 (s, H, ArH), 8.43 (d, H, ArH, J=7.24 Hz), 9.17 (s, H, ArH), 10.2 (sbr, H, NH). MS: (ESI+) MH+=324.14
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17]CC2C=CC=CC=2C)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH3:5]>C1COCC1.C(O)C.[Pd]>[OH:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2C)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Yield: 100.5 %

Procedure:
Methyl 3-{(1S)-2-methoxy-(1-methylethyl)oxy}-5-{[(2-methylphenyl)methyl]oxy}benzoate (50 g, 0.152 mol) was dissolved in THF/ethanol (1:1, 600 ml) and 10% Palladium on carbon (5.0 g) was added. The mixture was hydrogenated under normal pressure at room temperature. The catalyst was filtered off, and the filtrate concentrated in vacuo to give the desired compound (36.7 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5](O)=O.[NH:15]([C:17](=[S:19])[NH2:18])[NH2:16]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[S:19][C:17]([NH2:18])=[N:15][N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Oc1ccc(-c2nnc(N)s2)cc1Cl
Temperature: 75 °C
Reaction time: 3 h
Yield: 119.4 %

Procedure:
The mixture of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (5 g), hydrazinecarbothioamide (2.229 g) in phosphoric trichloride (21.43 g) was stirred at 75° C. for 3 h. Concentrated the mixture in vacuum to remove POCl3, the residue was poured into crush ice. Basified the mixture with aqueous NaOH. Extracted it with EA twice. The EA layer was concentrated in vacuum to give crude product 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-amine (D9) (7.5 g), which was used in the next step without further purification. MS (ES): C11H12ClN3OS requires 269. found 270.1 (M+H+).
Reaction SMILES: N1C=CC=CC=1N1CC2C(=O)N(CC(F)(F)F)C3C=CC=CC=3C=2N1C1CCCCO1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:39]=[CH:40][C:41]2[C:42]3[C:43](=[CH:54][N:55](C4CCCCO4)[N:56]=3)[C:44](=[O:53])[N:45]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:46]=2[CH:47]=1.[Cl:63]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)Cl>[Cl:63][C:39]1[C:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[CH:47][C:46]2[N:45]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:44](=[O:53])[C:43]3[CH:54]=[N:55][NH:56][C:42]=3[C:41]=2[CH:40]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1c2cn(C3CCCCO3)nc2c2ccc(-c3ccccn3)cc2n1CC(F)(F)F
Agent: O=c1c2c(c3ccccc3n1CC(F)(F)F)N(C1CCCCO1)N(c1ccccn1)C2
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1c2cn[nH]c2c2cc(Cl)c(-c3ccccn3)cc2n1CC(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
To a suspension of 7-(pyrid-2-yl-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [described in Step 1.5] (1.6 g, 3.73 mmol) in 32 mL of acetic acid is added N-chlorosuccinimide (2.49 g, 18.67 mmol). The reaction mixture is stirred for 3 hours at 80° C., cooled to room temperature and concentrated to dryness to give a yellow solid, which is dissolved in DCM. The solution is washed with saturated aqueous NaHCO3 solution and then with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated to give a yellow solid. The solid is taken up in DCM. After filtering off and drying, 542 mg of a white solid are obtained (yield: 35%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)c1ccc(Cl)nc1
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of 10 g (56.8 mmol) of 6-chloropyridine-3-carbonyl chloride in 100 mL of anhydrous toluene are added under argon, at room temperature, 15 g (170.4 mmol) of 2,2-dimethylpropanol. The reaction medium is then heated at 80° C. for 6 hours. After cooling to room temperature, the medium is concentrated and the residue obtained is taken up in 800 mL of EtOAc, washed successively with water (2×200 mL), with saturated NaHCO3 solution (2×200 mL) and with brine (100 mL), dried over Na2SO4, then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 5% EtOAc. 11.9 g of 2,2-dimethylpropyl 6-chloropyridine-3-carboxylate are obtained in the form of a white powder.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:14](=[O:28])[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([F:27])[CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)[CH2:9]1)C1C=CC=CC=1.CO.Br[CH2:40][C:41]1[C:46]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:44]=[CH:43][C:42]=1[Cl:51].C(=O)([O-])[O-].[K+].[K+]>[OH-].[Pd+2].[OH-].O.CN(C)C=O>[Cl:51][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([C:47]([F:50])([F:49])[F:48])[C:41]=1[CH2:40][N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])([C:14](=[O:28])[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([F:27])[CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)[CH2:9]1
Reactant: FC(F)(F)c1cccc(Cl)c1CBr
Reactant: CCCC(F)CN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3ccccc3)C[C@H]2C)CC1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(F)CN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3c(Cl)cccc3C(F)(F)F)C[C@H]2C)CC1
Temperature: 45 °C
Reaction time: 15 h
Yield: 78.9 %

Procedure:
A mixture of the chiral form of tert-butyl 2-[(3R*,4S*)-1-benzyl-3-{[1-(2-fluoropentyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetate obtained in Example 1k (161 mg, 0.32 mmol), 20% palladium hydroxide (135 mg) and methanol (5 ml) was stirred at mom temperature for 15 hours under a hydrogen atmosphere. The atmosphere in the reaction vessel was replaced with nitrogen, 20% palladium hydroxide was filtered off, and the solvent was distilled off. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (159 mg, 0.581 mmol), potassium carbonate (97 mg, 0.702 mmol) and N,N-dimethylformamide (2 ml) were added to the resulting residue, which was heated at 45° C. for three hours and 15 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate twice. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (153 mg, yield 78.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[N:21]1([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:25]=[CH:24][CH:23]=[CH:22]1>C(Cl)Cl.O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:22]1[N:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:25]=[CH:24][CH:23]=1)=[O:9]
Reactant: Cc1ccsc1C(=O)O
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccsc1C(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a stirred solution consisting of 3-methyl-2-thiophenecarboxylic acid (21.0 g) in dry DCM (1.5 l) was added oxalyl chloride (21.0 ml) at room temperature under nitrogen. After stirring for 1 hour at room temperature, the reaction mixture was cooled to -10° C. and tin (IV) chloride (17.3 ml) was added. The resulting solution was stirred for 10 minutes (-10° C.) at which time 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (31.3 g) was added in three portions. After stirring for 1 hour in the cooling bath, the reaction mixture was poured into cold water and the layers separated. The organic phase was washed twice with 5% HCl (aq.) and dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, DCM) afforded 12.5 g of the product as a solid, m.p. 221°-223° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.[BrH:13]>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Br:13]
Reactant: Br
Reactant: OCc1ccccc1C(F)(F)F
Solvent: O
Product: FC(F)(F)c1ccccc1CBr

Procedure:
A solution of 2-trifluoromethyl benzyl alcohol (1 g, 5.67 mmol) in aqueous HBr (6 mL) was stirred at 50° C. for 4 hrs. The reaction mixture was diluted with cold water and the product extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 780 mg of 2-trifluoromethylbenzyl bromide.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[Sn]Cl.O.Cl>C(O)C>[NH2:1][C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1-n1cccn1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccnc1-n1cccn1
Yield: 63.1 %

Procedure:
To a suspension of 3-nitro-2-(pyrazol-1-yl) pyridine (670 mg, 3.72 mmol) in ethanol (10 mL) was added a 1M solution of SnCl2.H2O in 6N aqueous HCl (14.5 mL, 14.5 mmol). The mixture was heated at reflux for 10 min, and the solvent was removed with a rotary evaporator. 10% aqueous sodium hydroxide solution was added until most of the material dissolved, and the mixture was extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated to afford 376 mg (68%) of 3-amino-2-(pyrazol-1-yl) pyridine as a brown oil. 1H NMR (CDCl3) δ5.62 (br s, 2 ), 6.46 (m, 1), 7.05 (dd, 1, J=5, 8), 7.24 (dd, 1, J=2, 8), 7.74 (m, 1), 7.85 (dd, 1, J=2, 5), 8.54 (d, 1, J=3).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16]P([O-])([O-])=O.[K+].[K+].C1C=C(Cl)C=C(C(OO)=O)C=1>ClC(Cl)C>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N+:12]=2[O-:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)n1
Reactant: O=P([O-])([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: CC(Cl)Cl
Product: O=C(O)c1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 60 °C
Yield: 68.2 %

Procedure:
A mixture of 6-phenylpicolinic acid (150 mg, 0.75 mmol), K2HPO4 (600 mg) m-CPBA (300 mg, max 70% from Aldrich) in dichloroethane (8.0 mL) was heated at 60° C. for 1.5 h. Additional m-CPBA (2×300 mg) was added and the mixture was heated at 60° C. for 40 min. The reaction mixture was purified by preparative HPLC to afford the desired product (110 mg, 68%) as a white solid. 1H NMR (DMF-d7) δ 8.57 (s, 1H), 8.43 (d, 1H, J=2.2 Hz), 8.10–7.88 (m, 5H), 7.59–7.57 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH:14]([CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:14]([CH3:15])[CH3:13])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: CCCC(N)CC(C)C
Product: CCCC(CC(C)C)NC(=O)c1ccc(OC)c(C)c1
Yield: 45 %

Procedure:
Prepared in a similar manner as described in example 4 using 4-methoxy-3-methylbenzoic acid and 2-methyl-4-heptanamine (example 2a). Yield: 45%. 1H NMR (500 MHz, CDCl3): δ 0.93 (m, 9H); 1.39 (m, 5H); 1.53 (m, 1H); 1.67 (m, 1H); 2.24 (s, 3H); 3.86 (s, 3H); 4.23 (m, 1H); 5.64 (d, 1H); 6.82 (d, 1H); 7.54 (s, 1H); 7.61 (d, 1H). MS (278 μM+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.C(Br)C1C=CC=CC=1>CS(C)=O.CCOCC.O>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Cc1ccccc1CBr
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
9-amino-3,4-dihydroacridin-1(2H)-one (7.63 g) was suspended in 75 ml of dimethylsulfoxide and 5 g of pulverized 85% potassium hydroxide was added. After 45 minutes a homogeneous solution was obtained to which was added 7.0 g of 2-methylbenzyl bromide. The reaction mixture was stirred for 30 minutes and then additional 2.0 g of the benzyl bromide was added. After 60 more minutes 300 ml of water and 30 ml of ether were added to the reaction. The precipitated product was filtered off and washed with additional ether, then flushed over a short magnesium silicate column with ethyl acetate. After evaporating the solvent, the product was again washed with cold ether to give 7.21 g of product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:9]([O:18][CH3:19])=[N:10][CH:11]=[C:12]([CH:17]=1)[C:13](OC)=[O:14].C(=O)([O-])O.[Na+]>O1CCCC1>[F:7][C:8]1[CH:17]=[C:12]([CH2:13][OH:14])[CH:11]=[N:10][C:9]=1[O:18][CH3:19]
Reactant: COC(=O)c1cnc(OC)c(F)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ncc(CO)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
To a suspension of 0.24 g of lithium aluminum hydride in 6 mL of tetrahydrofuran, a solution of 0.58 g of methyl 5-fluoro-6-methoxynicotinate in 3.5 mL of tetrahydrofuran was dropped under cooling with ice. After warming to room temperature, the mixture was stirred for 30 minutes. Thereto was dropped a saturated aqueous sodium hydrogen carbonate solution under cooling with ice, after stirring for 10 minutes, the reaction mixture was filtered through celite, and the filtration residue was washed with ethyl acetate and water. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.55 g of (5-fluoro-6-methoxypyridin-3-yl)methanol as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[CH:36]=[CH:35][N+:34]([O-:37])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:20][CH2:21][N:22]([C:31]4[CH:36]=[CH:35][N+:34]([O-:37])=[CH:33][CH:32]=4)[CH2:23][CH2:24]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Reactant: [O-][n+]1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCN(c2cc[n+]([O-])cc2)CC1
Temperature: 130 °C
Yield: 18 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (see stage 2 illustrative compound H-214) (200 mg, 0.486 mmol, 1 eq), 4-chloropyridine N-oxide (63 mg, 0.486 mmol, 1 eq) and DIPEA (0.210 ml, 1.215 mmol, 2.5 eq) in ethanol (10 ml) was heated for 72 h at 130° C. in a pressure vessel. The reaction mixture was concentrated under reduced pressure and the crude product was then prepurified by column chromatography (Alox, 1% methanol/dichloromethane). It was then further purified by means of preparative TLC. The desired product was in the form of a white solid. Yield: 18% (90 mg, 0.178 mmol) The indicated yield is based on 2 combined batches of size 200 mg
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]#[N:16].[H-].[Na+].Cl[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)C>CN(C)C=O.O>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:13]([CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]=2[CH:1]=1)#[N:16]
Reactant: CCOC(=O)C(C)Cl
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-phenothiazinecarbonitrile (224.5 g) in dimethylformamide (1 liter) is poured into a suspension of sodium hydride (24 g) in dimethylformamide (1 liter) at a temperature of about 25° C., whilst stirring and in 2 hours 30 minutes, then the mixture is stirred for a further 1 hour 15 minutes until evolution of gas has ended. The fine suspension obtained is poured, with stirring and at a temperature of about 25° C., in 4 hours 30 minutes into a solution of ethyl 2-chloropropionate (255 cc) in dimethylformamide (1 liter) and stirring is continued for 16 hours. Ethanol (100 cc) is then poured into the reaction mixture then the whole is poured onto a mixture of ice (2 kg) in distilled water (4 liters): a gum precipitates and then crystallizes. The solid formed is centrifuged, washed successively with distilled water (6×500 cc) and petroleum ether (2×500 cc) and dried in air. Ethyl (2RS)-2-(2-cyano-10-phenothiazinyl)propionate (296.5 g) is thus obtained in the form of khaki-colored crystals which melt at 117°-8° C., used as such in the following stage.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=C(N)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CC(O)=O>O>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[SH:10]
Reactant: Nc1nc2c(Cl)cccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(S)cccc1Cl
Temperature: 150 °C
Reaction time: 8 h

Procedure:
The 4-chlorobenzo[d]thiazol-2-amine (2.00 g, 10.83 mmol) was combined with KOH (10.0 g, 178.2 mmol) and H2O (20 mL). The rsulting mixture was heated at 150° C. overnight. The solid became a thick paste overnight. After 24 h, the mixture was allowed to cool to room temperatureand diluted with H2O. A solution of AcOH was added to bring the pH down to 4 to 5.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:29]([O:31]C)=[O:30])=[C:7]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1.[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O.N12CCCC1=NCCC2>C(#N)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:29]([OH:31])=[O:30])=[C:7]([CH:9]=[CH:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([Br:33])[CH:35]=2)[CH:8]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1ccc(Br)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: [Br-]
Solvent: CC#N
Product: O=C(O)c1ccc(Br)cc1C=Cc1cccc(Br)c1

Procedure:
The product of step (ii) (22.8 g). 3-bromobenzaldehyde (4.5 ml) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (5.95 g) in acetonitrile (50 ml) was heated under reflux for 0.5 hours. The solution was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with 2M HCl, dried (MgSO4) and evaporated. The residue and potassium hydroxide (5.6 g) in water (100 ml) and methanol (20 ml) was heated under reflux for 8 hours. The reaction mixture was diluted with water and washed with dichloromethane. The aqueous solution was acidified to pH 1 (2N HCl) and extracted with dichloromethane. The organic solution was dried (MgSO4), evaporated and the product purified by chromatography eluting with toluene. Yield 8.5 g. Used directly in the next step.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][N:6]=1>C(Cl)(Cl)Cl>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:12][C:2]#[N:1])=[CH:9][CH:10]=1
Reactant: N#CBr
Reactant: NCc1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: N#CNCc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cyanogen bromide (220 mg, 2.09 mmol) was dissolved in 10 mL of anhydrous chloroform, and the solution was cooled to 0° C. To this was dropwise added a solution of 500 mg (3.49 mmol) of 2-chloro-5-aminomethylpyridine dissolved in 10 mL of anhydrous chloroform, and the resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was filtered, then water was added and liquid-liquid extraction was carried out, following which the chloroform phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=1:1), giving 122 mg (yield, 35%) of the target compound.