Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:29])[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]=2[CH:9]=1)=S)[CH2:2][CH2:3][CH3:4].C(O)(=[O:32])C>C(OCC)C>[CH2:1]([NH:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:22]([CH3:29])[CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]=2[CH:9]=1)=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: CCOCC
Product: CCCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 5 h

Procedure:
A suspension of N-butyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1.2 g) and mercuric acetate (1 g) in acetic acid (15 cc) is stirred for 5 hours at a temperature in the region of 20° C. The black suspension obtained is diluted with ethyl ether (25 cc) and filtered. The solid is washed with ethyl ether (2×10 cc). The combined organic phases are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is taken up with ethyl acetate (25 cc) and distilled water (25 cc). The organic phase is separated, filtered, dried over magnesium sulphate, filtered again and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The very viscous residual oil (1.1 g) is taken up with a mixture (83:17 by volume) (12 cc) of ethyl acetate and methanol warmed to about 50° C. After 1 hour at a temperature in the region of 20° C., the solid formed is drained, washed with diethyl ether (2×10 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-butyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]- 2-phenothiazinecarboxamide (0.4 g) is thereby obtained in the form o cream-coloured crystals, m.p. 218° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76]2([NH:80][S:81]([C:83]([CH3:86])([CH3:85])[CH3:84])=[O:82])[CH2:79][O:78][CH2:77]2)=[CH:72][CH:71]=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:85][C:83]([CH3:86])([S:81]([NH:80][C:76]1([C:73]2[CH:74]=[CH:75][C:70]([NH:69][C:2]3[N:7]=[C:6]([CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=3)=[CH:71][CH:72]=2)[CH2:79][O:78][CH2:77]1)=[O:82])[CH3:84]
Reactant: CC(C)(C)S(=O)NC1(c2ccc(N)cc2)COC1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(C3(NS(=O)C(C)(C)C)COC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 150 °C

Procedure:
A suspension of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6) (200 mg, 0.690 mmol), Pd(OAc)2(16 mg, 0.069 mmol), Xantphos (59.9 mg, 0.104 mmol), Cs2CO3 (648 mg, 1.99 mmol) and N-(3-(4-aminophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (A121) (204 mg, 0.759 mmol) in 1,4-dioxane (1.73 mL) was heated under microwave irradiation for 10 minutes at 150° C. under nitrogen. The resulting mixture was filtered through Celite, washing with EtOAc. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (CombiFlash Rf, SiO2 cartridge, 0-30% MeOH in DCM) to give the title compound A122 (102 mg, 28%); 1H NMR (300 MHz, d4-MeOH) δ 8.07 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H), 7.19 (m, 4H), 5.17 (d, J=6.6 Hz, 1H), 5.07 (d, J=6.5 Hz, 1H), 5.03 (d, J=6.7 Hz, 1H), 4.93 (d, J=6.4 Hz, 1H), 3.64 (s, 2H), 3.12 (m, 2H), 2.95 (m, 2H), 2.07 (s, 3H), 1.27 (s, 9H). LCMS-B: rt 5.80 min; 522.2 m/z [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(F)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3,4-difluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.24 (s, 1H), 7.28 (q, J=9.2 Hz, 1H), 7.11 (dd, J=8.7, 2.4 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 6.90 (m, 2H), 6.74 (m, 1H), 3.26 (s, 3H), 1.97 (m, 4H), 0.81 (t, J=7.3 Hz, 6H). MS (ESI) m/z [M+H]+ (347); MS (ESI) m/z [M−H]−(345); Anal. calcd for C19H20F2N2O2: C, 65.88; H, 5.82; N, 8.09. Found: C, 65.30; H, 5.71; N, 7.79.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:4]=1[O:5][CH3:6])[CH3:2].[OH:12][C:13]1C2C(=C(C)C(OC)=CC=2)N=[C:15]([C:26]2[S:27][CH:28]=[C:29]([CH:31]([CH3:33])[CH3:32])[N:30]=2)[CH:14]=1>>[CH2:1]([C:3]1[C:4]([O:5][CH3:6])=[CH:7][CH:8]=[C:9]2[C:10]=1[N:11]=[C:15]([C:26]1[S:27][CH:28]=[C:29]([CH:31]([CH3:32])[CH3:33])[N:30]=1)[CH:14]=[C:13]2[OH:12])[CH3:2]
Reactant: CCc1c(N)cccc1OC
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: CCc1c(OC)ccc2c(O)cc(-c3nc(C(C)C)cs3)nc12

Procedure:
The title compound was prepared from 2-ethyl-m-anisidine (68) following the procedure (Steps 3-5) reported for the preparation of 4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinoline (36): m/z=329 (M+H)+.
Reaction SMILES: [CH2:1]([N:6]1[C:11](=[O:12])[NH:10][CH:9](OC)[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]>C1(C)C=CC=CC=1>[CH2:1]([N:6]1[C:11](=[O:12])[N:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[N:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1N=C(c2ccc(Cl)cc2)C(OC)NC1=O
Solvent: Cc1ccccc1
Product: CCCCCn1nc(-c2ccc(Cl)cc2)cnc1=O

Procedure:
A 0.5 g sample of 2-pentyl-5-methoxy-6-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-3-one was dissolved in toluene. The toluene was removed from the product by distillation at atmospheric pressure to give 0.28 g of 2-pentyl-6-(4-chlorophenyl)-1,2,4-triazin-3-one (Compound 2).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][NH:9][C:10]2[C:15]([I:16])=[C:14]([CH3:17])[CH:13]=[CH:12][N:11]=2)=O)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C(OCC)(=O)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[C:15]([I:16])[C:10]3=[N:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccnc(NNC(=O)NCC2CC2)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccn2c(NCC3CC3)nnc2c1I
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of N-(cyclopropylmethyl)-2-(3-iodo-4-methylpyridin-2-yl)hydrazinecarboxamide (preparation 28c, 0.85 g, 2.5 mmol) and phosphorous oxychloride (10 mL) was stirred at 75° C. overnight. The reaction mixture was cooled to ambient temperature and added slowly to an ice-water mixture and then ethyl acetate was added. To the cooled, stirred, biphasic mixture was added aqueous sodium hydroxide solution until the aqueous layer reached a pH of 8. The organic layer was washed with water, brine, dried (MgSO4) and the solvent evaporated in vacuo to yield the title compound (0.77 g, 96%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH2:32][CH2:33][C:34]([C:10]2[C:11]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=3[S:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:35])[CH:23]=[C:22]([O:21][CH3:20])[C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1cc(CCC(=O)Cl)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)CCc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
To a well-stirred solution of 2-(4′-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.206 g, 0.762 mmol) and 3-(3′,4′,5′-trimethoxyphenyl)propionyl chloride (0.390 g, 1.51 mmol) in CH2Cl2 (50 mL) was added AlCl3 (0.520 g, 3.89 mmol) portion-wise over a 15 minute period. After 18 hours (total reaction time), water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed sequentially with NaHCO3 (sat) and brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 70:30 EtOAc/hexane) afforded the title compound as an off-white solid. 1H-NMR (CDCl3, 360 Mhz): δ=7.92 (d, J=8.9 Hz, 1H, ArH), 7.35 (d, J=8.7 Hz, 2H, ArH), 7.25 (m, 1H, ArH), 7.04 (dd, J=8.9, 2.4 Hz, 1H, ArH), 6.93 (d, J=8.7 Hz, 2H, ArH), 6.15 (s, 2H, ArH) 3.88 (s, 3H, —OCH3), 3.85 (s, 3H, —OCH3), 3.78 (s, 3H, —OCH3), 3.72 (s, 6H, —OCH3), 3.80 (t, 2H, CH2), 3.70 (t, 2H, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:12]=[CH:11][N:10]([CH3:22])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(-c2nc[nH]c2-c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4,5-di-(2,4-dichlorophenyl)imidazole (230 mg, 0.65 mmol) from Step B and methyl iodide (0.062 mL, 1.0 mmol) in DMF (5 mL) was added sodium hydride (60% in mineral oil, 52 mg, 1.3 mmol). The reaction was stirred at rt for 3 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (50% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([C:9]([OH:11])=O)[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:44][CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1>CN(C)C=O>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([C:9]([NH:44][CH:45]3[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50]3)=[O:11])[O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1nc2ccc(O)cc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a stirred mixture of 6-hydroxybenzo[d]oxazole-2-carboxylic acid (0.15 g, 0.86 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added triethylamine (0.10 g, 0.99 mmol), 1-hydroxybenzotriazole hydrate (0.14 g, 0.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20 g, 0.99 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.20 g, 0.99 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford tert-butyl 4-(6-hydroxybenzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate as a off-white solid (0.16 g, 52%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.10 (s, 1H), 9.04 (m, 1H), 7.63 (m, 1H), 7.10 (m, 1H), 7.27 (m, 5H), 6.91 (m, 1H), 3.92 (m, 3H), 2.78 (m, 2H), 1.72 (m, 2H), 1.49 (m, 2H), 1.38 (s, 9H); MS (ESI): 362.1 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44]([C:46]1[N:50]([CH3:51])[N:49]=[CH:48][CH:47]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][C:46]4[N:50]([CH3:51])[N:49]=[CH:48][CH:47]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Reactant: Cn1nccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2ccnn2C)cc1
Reaction time: 120 h
Yield: 60.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 5-formyl-1-methylpyrazole (0.23 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 5 days. To the reaction solution, 5-formyl-1-methylpyrazole (0.23 g) and sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) were added, and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:3) and further recrystallized from ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(1-methylpyrazol-5-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 89) (140.1 mg) as yellow crystals.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[CH:13]4)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([C:7]3[S:6][C:5]4=[N:4][CH:3]=[C:2]([C:27]5[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=5)[N:9]4[N:8]=3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: Ic1cnc2sc(-c3ccc4[nH]ccc4c3)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnc3sc(-c4ccc5[nH]ccc5c4)nn23)cc1C(F)(F)F
Temperature: 110 °C
Yield: 12.1 %

Procedure:
A mixture of 5-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1H-indole (0.091 g, 0.247 mmol, 1 eq), 5-(4,4,5,5-tetramethyl[-1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (0.107 g, 0.371 mmol, 1.5 eq), 2M aq Na2CO3 (1 mL) and PdCl2(PPh3)2 (0.035 g, 0.049 mmol, 0.2 eq) in dioxane (5 mL) was heated at 110° C. for 24 h. The solvent was removed in vacuo, redissolved in DCM/water (150 mL) and extacted with DCM (2×80 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (0-10% MeOH in DCM and a second column 0-5% MeOH in DCM) to afford the desired product (12 mg, 12%) as a yellow solid. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.08 min, [M+H]+ m/z 401.0; 1H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.90 (d, J=1.8 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.75 (s, 1H), 7.73 (dd, J=9.2, 2.4 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.52 (m, 1H), 6.73 (s, 2H), 6.64 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.O1CCCC1.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[CH2:7][OH:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 101.5 %

Procedure:
12 g of 5-bromo-2-chorobenzoic acid was dissolved in 60 ml tetrahydrofuran, and 148.3 g of borane-tetrahydrofuran complex (1 M solution in tetrahydrofuran) was added, followed by stirring at room temperature for 2.5 days. 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated, to give 11.46 g of 5-bromo-2-chlorobenzyl alcohol. This crude product was treated in the same method as in Production Example 89e), to give ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methylphenyl)-2-isopropoxypropionate.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:28][C:25]4[S:26][CH:27]=[C:23]([C:22]([F:31])([F:30])[F:21])[N:24]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: OCc1nc(C(F)(F)F)cs1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cc2n1C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (400 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (544 mg) and triphenylphosphine (1.17 g) in THF (35 ml) was added bis(2-methoxyethyl) azodicarboxylate (1.04 g) at room temperature. After 3 h, the mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/MeOH), followed by recrystallization from IPA-IPE to give the title compound (175 mg) as a white solid.
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6](CCC(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.C(N1[C:40]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3N=C(N)C=2N=C1CCOC)CCC.C(N1C2C3C=CC=CC=3N=C(N)C=2N=C1COCC)CCC.NC1C2N=C(CO)N(CCCC)C=2C2C=CC=CC=2N=1>>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([CH2:40][C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCC(C)C
Agent: CCCCn1c(CO)nc2c(N)nc3ccccc3c21
Agent: CCCCn1c(COCC)nc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1nc(CO)n2Cc1ccccc1

Procedure:
A compound according to claim 1, selected from the group consisting of 2-ethoxymethyl-1-(3-methylbutyl)-1H-imidazo[4,5-c]quinolin-4-amine, 1-butyl-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine, 1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine, and 4-amino-1-butyl-1H-imidazo[4,5-c]quinoline-2-methanol,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([CH:14]=O)=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[N:11]=[C:10]([S:24][CH3:25])[N:9]=1.[CH3:26][C:27](OC(C)=O)=[O:28]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH:14]=[CH:26][C:27](=[O:28])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:12]=2[N:11]=[C:10]([S:24][CH3:25])[N:9]=1
Reactant: CSc1nc(Nc2ccccc2F)c(C=O)c(-c2ccccc2F)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CSc1nc(-c2ccccc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Yield: 76 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde, as described in Example 22, (400 mg, 1.1 mmol) in pyridine (2 mL) was added Ac2O (2 mL) and the reaction mixture was heated under reflux for 48 h, solvent was evaporated and the residue was dissolved in EtOAc (40 mL), washed with 1 M aq Na2CO3, and H2O and satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was purified by Flash chromatography to afford pure 4,8-bis-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (320 mg, 76% yield). 1H-NMR (CDCl3) δ 2.21 (s, 3H), 6.76 (d, 1H, J=9.6 Hz), 7.22-7.42 (m, 4H), 7.45-7.67 (m, 5H). LC MS (m/e)=382 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][C:21](N)=[O:22])=[O:19].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:21]([NH:20][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)=[O:19])=[O:22])[CH2:5]2
Reactant: NC(=O)NC(=O)c1ccccn1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccccn1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 14b, from 3-aminoquinuclidine dihydrochloride (1.0 g, 5 mmol), 2-pyridoylurea (0.82 g, 5 mmol) and di-isopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml) by refluxing for 4 days. The pyridine was evaporated and the residue partitioned between ether and 10% aqueous w/v citric acid. The mixture was filtered, the aqueous phase washed with ether, then basified with potassium carbonate to precipitate the title compound (0.60 g) which was converted to the 1:1 fumarate, mp 202°-203° C.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([N:22]4[C:30](=[O:31])[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:32]#[N:33])[CH:28]=5)[CH2:23]4)=[CH:20][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C(Cl)Cl.CO>[NH2:33][CH2:32][C:27]1[CH:28]=[C:29]2[C:24]([CH2:23][N:22]([C:21]3[C:15]4[C:16](=[N:17][CH:18]=[C:13]([C:10]5[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=5)[N:14]=4)[NH:19][CH:20]=3)[C:30]2=[O:31])=[CH:25][CH:26]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4ccc(C#N)cc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(N4Cc5ccc(CN)cc5C4=O)c3n2)cc1
Reaction time: 2 h

Procedure:
2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]-3-oxo-isoindoline-5-carbonitrile (130 mg, 0.1858 mmol) dissolved in a mixture of DCM (10 mL) and MeOH (5 mL) under N2. CoCl2 (48.25 mg, 0.3716 mmol) added then the reaction mixture cooled in an ice bath. NaBH4 (70 mg, 1.858 mmol) added in one portion. Ice bath removed and mixture stirred for 2 h then cooled in an ice bath and water (˜5 mL) added. Mixture diluted with DCM (˜20 mL) and stirred vigorously for 20 mins. Layers separated and aqueous extracted with DCM. Aqueous phase basified by addition of sat NaHCO3 solution and extracted with DCM (×2). Combined organics dried and concentrated to a brown foam. This material deprotected using Method E Step 2 to give the title compound after purification by hplc; 1H NMR (400 MHz, DMSO) δ 1.21 (6H, d), 3.50 (1H, sep), 3.88 (2H, s), 5.49 (2H, s), 7.65 (1H, d), 7.71 (1H, d), 7.84 (1H, s), 8.00 (2H, d), 8.51-8.53 (3H, m), 9.09 (1H, s) ppm; MS (ES+) 462.0.