Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:35][CH2:36][C:37]1[C:38]([OH:45])=[N:39][C:40]([CH3:44])=[CH:41][C:42]=1[CH3:43]>ClCCl>[C:1]([NH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:35][CH2:36][C:37]2[C:38]([OH:45])=[N:39][C:40]([CH3:44])=[CH:41][C:42]=2[CH3:43])=[O:13])=[CH:14][CH:15]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 20 °C
Reaction time: 13 h
Yield: 135.6 %

Procedure:
To a solution of 4-(1-acetamidoethyl)benzoic acid (414 mg, 2.0 mmol), 1-hydroxybenzotriozole (405 mg, 3.0 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.0 mmol), triethylamine (0.83 mL) in dichloromethane (30 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (82 mg, 0.54 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-(1-acetamidoethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (250 mg, 37%). LRMS (M+H+) m/z: calcd 341.17. found 341. HPLC Purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.35-8.26 (m, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 5.85 (s, 1H), 4.90 (q, J=7.2 Hz, 1H), 4.28 (d, J=5.1 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H), 1.83 (s, 3H), 1.1 (d, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1>CN(C)C=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)=[N:31][CH:32]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)cn1
Reactant: Fc1ccc(CCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)cc3)no2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To 4-(5-(6-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 177-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.9 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of the solid obtained above and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of the 2-chloromethyl-5-fluoro-pyridine (12.0 mg, 0.08 mmol) described in Manufacturing Example 41-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (3.0 mg, 11%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[Br:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[Br:17])=[CH:6][CH:5]=1)([OH:3])[CH3:2])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(-c2ccc(Br)cc2Br)cc1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Br)cc2Br)cc1

Procedure:
3.44 g. of 4-acetyl-2',4'-dibromobiphenyl and 1.5 g. of ethyl bromoacetate are added to a mixture of 6.5 g. of granulated zinc, previously washed with dilute hydrochloric acid, water and acetone and dried, and 0.2 g. of iodine in 70 ml. of benzene and 70 ml. of diethyl ether. The mixture is heated under reflux for 4 hours with occasional shaking. 5 g. of zinc and a trace of iodine are added after 1, 2 and 3 hours, respectively, and 1.5 g. of ethyl bromoacetate added after 2 hours. After cooling, acetic acid is added to decompose the resulting alcoholate and methanol is added to bring the product into solution. The mixture is poured into water and the organic phase is separated off and worked up to give 3-(2',4'-dibromo-4-biphenylyl)-3-hydroxybutyric acid ethyl ester.
Reaction SMILES: [CH:1](/[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1>O=[Pt]=O.C1COCC1>[CH2:1]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: COc1cc(CCc2ccc(O)c(OC)c2)ccc1O
Yield: 91 %

Procedure:
A Parr reaction vessel was charged with (E)-4,4′-(ethene-1,2-diyl)bis(2-methoxyphenol) (2.85 g, 10.5 mmol), THF (50 mL), PtO2 (70 mg), and then placed under hydrogen (30 psig) and allowed to react at ambient temperature for 16 h with continuous agitation. The mixture was filtered through glass wool to remove platinum and the THF was removed under reduced pressure. The solid was washed with hexanes (2×30 mL) and dried under reduced pressure to afford 2.62 g of light brown solid (91% yield). 1H NMR (DMSO-d6) δ 8.66 (s, 2H, Ph-OH), 6.73 (s, 2H), 6.65-6.53 (m, 4H), 3.70 (s, 6H, OMe), 2.70 (s, 4H, CH2); 13C NMR (DMSO-d6): δ 147.7, 144.9, 133.1, 120.9, 115.6, 113.1, 56.0 (OMe), 37.6 (CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:20][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]3[S:10][C:11]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=4[N:13]=3)=[C:6]([Cl:19])[CH:5]=2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Cl)c(Oc3nc4ccc(Cl)cc4s3)c(Cl)c2)cc1

Procedure:
4-Acetyl-N-[3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenyl]-benzenesulfonamide was synthesized (36%) from 3,5-dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (420) and 4-acetyl-benzenesulfonyl chloride (Fluka) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (br s, 1H), 8.18 (dd, J=7.8, 1.7 Hz, 2H), 8.15 (d, J=2.2 Hz, 1H), 8.01 (d, J=7.8, 1.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.32 (s, 2H), 2.63 (s, 3H). MS (EI): m/z 525 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][CH2:13][C:14](OCC)(OCC)OCC>COCCOCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:12][CH2:13][C:14]1[O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[N:1]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOCCOC
Solvent: O
Product: O=[N+]([O-])c1cccc2oc(CCl)nc12
Temperature: 25 °C
Yield: 17.9 %

Procedure:
To a RT solution of 2-amino-3-nitrophenol (14.7 g, 95 mmol, 1.0 equiv) in 2-methoxyethylether (136 mL) was added 2-chloro-1,1,1-triethoxyethane (19.1 g, 97.3 mmol, 1.02 equiv) and p-toluene sulfonic acid hydrate (25 mg, 0.13 mmol, 0.2 equiv). The resulting mixture was heated to reflux overnight. After the reaction was cooled to RT, the solvent was removed in vacuo. The solid was suspended in methanol (40 mL), stirred and filtered to provide the desired product as a red solid (3.61 g). The filtrate provided an additional 9.8 g of the title compound through an additional methanol treatment (13.4 g, 98% combined).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CCO.O>[C:1]([O:4][CH:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
To a solution of 100 mg. (0.303 mmol) of 3-acetoxy-androst-5-en-17-one, 1, in 3 ml EtOH at -10° C., was added 22.9 mg (0.606 mmol) of sodium borohydride with stirring. After the reaction mixture was stirred for one and 1/2 hours, the mixture was diluted with 10 ml water, the ethanol solvent removed under vacuum, and the residue extracted with ethyl acetate. The organic layer was washed with aqueous Na2CO3, brine, dried over sodium sulfate and concentrated to leave a residue of crude title compound. Proton NMR confirmed the assigned structure.
Reaction SMILES: [CH:1]1([N:6]2[CH:12]([CH3:13])[CH:11]([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH:67]1[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH:12]([CH3:13])[CH:11]([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:67]5[CH2:72][CH2:71][N:70]([CH3:73])[CH2:69][CH2:68]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)C(C)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)C(C)C(=O)N2C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
A mixture of 0.095 g (0.00022 mole) of (rac)-4-(9-cyclopentyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-41a), 0.90 g (0.00024 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.132 mL (0.0076 mole) of ethyldiisopropyl amine and 2.0 mL of dimethylformamide was stirred for 5 minutes and then 0.037 g (0.00033 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (10:90-80:0) to give 0.086 g of (rac)-4-(9-cyclopentyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-41) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round bottom flask fitted with a condensor and addition funnel, N-methylpiperazine (10.0 grams, 0.1 mol) was stirred while 2-fluoronitrobenzene (14.1 grams, 0.1 mol) was added dropwise under nitrogen. Caution—a vigorous exotherm occurred when approximately 20% of the 2-fluoronitrobenzene had been added. Following completion of the addition (˜30 min.) the reaction was stirred another 60 min. at room temperature, diluted with methylene chloride (100 mL) and washed with saturated aqueous Na2CO3 and saturated aqueous sodium chloride. After drying with MgSO4, the solvent was removed in vacuo to give 2-(4-methylpiperazin-1-yl)-1-nitrobenzene as an orange oil, 20.4 grams. Mass spectrum: 221 (M+). 174 (M-HNO2) 1H-NMR (CDCl3, 300 MHz) δ 7.8-7.0 (4H, m), 3.05 (4H, m), 2.55 (4H, t), 2.3 (3H, s).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:40])([C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:35]=[CH:36][N:37]([CH3:39])[CH:38]=3)=[CH:30][CH:29]=2)=[C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]2=[O:26])=[CH:12][CH:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:35]=[CH:36][N:37]([CH3:39])[CH:38]=3)=[CH:30][CH:29]=2)=[C:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]2=[O:26])=[CH:12][CH:11]=1)([CH3:40])[CH3:9]
Reactant: Cn1cnc(-c2ccc(NC(=C3C(=O)Oc4ccccc43)c3ccc(C(C)(C)NC(=O)OC(C)(C)C)cc3)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cnc(-c2ccc(NC(=C3C(=O)Oc4ccccc43)c3ccc(C(C)(C)N)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g of tert-butyl(1-methyl-1-{4-[[4-(1-methyl-1H-imidazol-4-yl)phenylamino]-(2-oxobenzofuran-3-ylidene)methyl]phenyl}ethyl)carbamate (N-Boc derivative of Example 56) was dissolved in 50 mL of dioxane and combined with 50 mL of a 4N solution of hydrogen chloride in dioxane. The solution was stirred for 1 hour at RT and evaporated down. The residue was dissolved in 50 mL of methanol and evaporated down with another 150 mL of isopropanol almost to the residue and then crystallized. After diluting with acetone, the product was suction filtered and washed with acetone. Yield: 1.9 g of yellow crystals of melting point>280° C. as hydrochloride; Rf value: 0.18 (dichloromethane/methanol (8:2)).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([N:53]1[CH:57]=[C:56]([C:58]2[C:66]3[C:61](=[N:62][CH:63]=[C:64]([C:67]4[CH:68]=[CH:69][C:70]([N:73]5[CH2:78][CH2:77][N:76]([CH2:79][C@@H:80]([OH:82])[CH3:81])[CH2:75][CH2:74]5)=[N:71][CH:72]=4)[CH:65]=3)[N:60](S(C3C=CC(C)=CC=3)(=O)=O)[CH:59]=2)[CH:55]=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:46]([N:53]1[CH:57]=[C:56]([C:58]2[C:66]3[C:61](=[N:62][CH:63]=[C:64]([C:67]4[CH:68]=[CH:69][C:70]([N:73]5[CH2:74][CH2:75][N:76]([CH2:79][C@@H:80]([OH:82])[CH3:81])[CH2:77][CH2:78]5)=[N:71][CH:72]=4)[CH:65]=3)[NH:60][CH:59]=2)[CH:55]=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6ccccc6)c5)c4c3)cn2)CC1
Yield: 33.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-benzyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl)propan-2-ol (155 mg, 0.239 mmol) was hydrolyzed with lithium hydroxide (50 mg, 1.19 mmol) in THF/methanol/water (4/4/2 mL) to yield 40 mg (24.9% yield) of desired product. 1H NMR (DMSO-d6, 300 MHz): δ 11.8 (s, 1H), 9.6 (s, 1H), 8.63-8.62 (d, 1H), 8.52-8.51 (d, 1H), 8.42 (s, 1H), 8.36-8.35 (d, 1H), 8.11-8.07 (dd, 1H), 7.97 (s, 1H), 7.769-7.761 (d, 1H), 7.38-7.27 (m, 4H), 7.10-7.07 (d, 1H), 5.38 (s, 2H), 4.47-4.35 (m, 2H), 4.20-4.10 (m, 1H), 3.50-3.00 (m, 6H), 1.15-1.13 (d, 3H). MS: m/z=494.6 (M+1), HPLC: 96.64% in method B.
Reaction SMILES: [Si:1]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:20]=[O:21].[Cl-].[NH4+]>CCOCC>[Si:1]([C:8]1[S:9][C:10]([CH:20]=[O:21])=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)c1nccs1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)c1ncc(C=O)s1
Temperature: -40 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of compound Q (40 g) in ether (100 ml) was added dropwise to a solution of n-butyllithium (1.6M solution in hexane, 138 ml) in ether (300 ml) at -70° C. under an atmosphere of argon. The mixture was stirred for 1 hour at this temperature and then N,N-dimethylformamide (30 ml) was added dropwise. The mixture was stirred for 30 minutes at -70° C., then warmed to -40° C. Excess saturated aqueous ammonium chloride solution was added and the mixture allowed to warm to ambient temperature. The layers were separated and the aqueous phase extracted three times with ether. The organic phases were combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography, eluting with 25% ethyl acetate/hexane (v/v), to give 2-tert-butyldimethylsilylthiazole-5-carboxaldehyde (R) (31 g, 69% yield) as an oil; NMR: 0.32(6H,s), 0.89(9H,s), 8.55(1H,s), 10.0(1H,s).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[C:9]1=[O:30].C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][N:10]1[C:11]2[C:12](=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[N:8]([C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[CH3:1])[C:9]1=[O:30]
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)n(Cc2cccc([N+](=O)[O-])c2)c2cnc3[nH]ccc3c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)n(Cc2cccc(N)c2)c2cnc3[nH]ccc3c21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of rel-1-[(1S,2R)-2-methylcyclohexyl]-3-(3-nitrobenzyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (150 mg) in a mixed solution of ethanol (1.5 mL) and water (0.45 mL) were added iron powder (62 mg) and ammonium chloride (10 mg). The solution was refluxed for 3 hours. After cooling to ambient temperature, the precipitate was filtered through a pad of Celite. After concentration under reduced pressure, the residue was extracted with chloroform and washed with water and dried over MgSO4. Concentration under reduced pressure to give 3-(3-aminobenzyl)-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]-pyridin-2(1H)-one (139 mg) as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[CH:44]([C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50])([CH3:46])[CH3:45]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([NH:50][C:49]4[CH:51]=[CH:52][CH:53]=[C:47]([CH:44]([CH3:46])[CH3:45])[CH:48]=4)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1
Reactant: CC(C)c1cccc(N)c1
Reactant: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)O)c1)C3
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)Nc2cccc(C(C)C)c2)c1)C3
Reaction time: 0.08 h
Yield: 16.6 %

Procedure:
To a mixture of 3-(8,9-dimethoxy-1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid hydrochloride (0.25 mmol, 100 mg) and N, N-diisopropylethylamine (0.75 mmol, 0.131 mL) in 2.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.325 mmol, 0.193 mL). After 5 min at rt, 3-isopropylaniline (0.375 mmol, 0.053 mL) and catalytic DMAP was added and the reactions continued for 2 hours. Then an additional 0.050 mL propylphosphonic anhydride solution and 0.025 mL 3-isopropylaniline was added and the reaction continued for 19 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3/EtOAc and then recrystallized from EtOAc/hexane to give the title compound as a white solid (20 mg, 17%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1.CCN(C(C)C)C(C)C>C(O)(C)C>[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][C:2]2[C:3]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]4[S:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:13][CH:14]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27]1
Reactant: Clc1nccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: NC1CCCOC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2sc(Nc3ccc(Oc4nccnc4NC4CCCOC4)cc3)nc2c1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
To a microwave vial was charged with N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.25 g, 0.71 mmol), tetrahydro-2H-pyran-3-amine hydrochloride (0.19 g, 1.4 mmol), and DIPEA (0.49 mL, 2.8 mmol) in isopropyl alcohol (2 mL). The reaction was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 200° C. for 30 min (200 watts, Powermax™ feature on), then at the same temperature for another 15 min. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (3×) and the combined organics was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(4-(3-(tetrahydro-2H-pyran-3-ylamino)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as off-white solid. MS (ESI, pos. ion) m/z: 420.0 (M+1). IC50 (uM) ++++.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:29])=[C:12]([CH:28]=2)[CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@@H:15]2[CH3:27])[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[F:29][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:7]=2)=[CH:28][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]1[CH3:27]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(-c2ccnc(Cl)n2)ccc1F
Reactant: NCCc1ccc(O)cc1
Product: C[C@H]1CNCCN1Cc1cc(-c2ccnc(NCCc3ccc(O)cc3)n2)ccc1F

Procedure:
Intermediate 166 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 422. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.7 (d, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.6 (d, 1H), 7.5 (t, 1H), 7.1 (d, 2H) 6.6 (d, 1H), 3.9-3.7 (m, 3H) 3.69-3.57 (m, 8H), 2.9 (t, 2H), 1.7 (d, 3H).