Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([NH:31][CH2:32][CH2:33][CH3:34])[N:26]=[C:25]([S:35][CH2:36][C:37]3[N:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=4)[S:40][CH:41]=3)[C:24]=2[C:49]#[N:50])=[CH:19][CH:18]=1)=[O:12])[CH3:10])=O)(C)(C)C.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>ClCCl>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[NH2:8][C@H:9]([C:11]([O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[C:27]([NH:31][CH2:32][CH2:33][CH3:34])[N:26]=[C:25]([S:35][CH2:36][C:37]3[N:38]=[C:39]([C:42]4[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=4)[S:40][CH:41]=3)[C:24]=2[C:49]#[N:50])=[CH:19][CH:18]=1)=[O:12])[CH3:10]
Reactant: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc2)c1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)N)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
873 mg (1.191 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(propylamino)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alaninate (Example 14A) were initially charged in 29 ml of dichloromethane. 1.84 ml (23.817 mmol) of trifluoroacetic acid were added, and the reaction solution was then stirred at RT overnight. The reaction solution was concentrated by evaporation and the residue was triturated with diethyl ether. The solid formed was filtered off and dried. This gave 914 mg (89% of theory) of the target compound.
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].FC(F)(F)C(O)=O.S([O-])([O-])(=O)=O.[Mg+2].N(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>>[Cl:8][C:3]1[C:2]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: OCC(F)(F)F
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1cccnc1Cl
Temperature: 15 °C

Procedure:
A reactor vessel is charged with 3-amino-2-chloropyridine (2.7 g, 21 mmol), 2,2,2-trifluoroethanol (15 g, 150 mmol), and trifluoroacetic acid (3.63 g, 31.8 mmol). The solution is cooled to 15° C. and magnesium sulfate (2.6 g) is charged to the vessel. The reagent t-butyl nitrite (2.51 g of a 96% solution, 23.4 mmol) is added drop-wise to the vessel while maintaining the temperature in the range 15° C. to 20° C. The solution is neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The solvent is removed by evaporation to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (1.58 g, crude yield 35.6%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH:16]=[CH:17][CH2:18][CH2:19][CH3:20])=[C:4]([CH3:21])[N:3]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([CH3:21])[N:3]=1
Reactant: CCCC=Cc1c(C)nc(C)c(CO)c1-c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C)nc(C)c(CO)c1-c1ccccc1

Procedure:
The title compound was prepared from 2,6dimethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (Example 3) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.42 (m, 3 H), 7.15 (m, 2 H), 4.33 (s, 2 H), 2.65 (s, 3 H), 2.56 (s, 3 H), 2.27 (m, 2 H), 1.29 (m, 2 H), 1.11 (m, 4 H), 0.76 (t, J =7 Hz, 3 H). EI-MS: calculated for (C19H25NO) 283, found 283 (M+). Anal. calculated for C19H25NO: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.39; H, 8.85; N, 4.85. mp 99-100° C. Rf=0.3 (90% ethyl acetate/hexane).
Reaction SMILES: [CH3:1]C1(C)[C@@H]2O[C@@H]2C2C=C(C#N)C=CC=2O1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[C@H:24]([OH:29])[C@@H:23]([N:30]([CH2:37][C:38]([O:40][CH2:41]C)=[O:39])C3C=CC=CC=3)[C:22]=2[CH:43]=1)#[N:17]>>[CH3:41][O:40][CH:38]([O:39][CH3:1])[CH2:37][NH:30][C@H:23]1[C:22]2[CH:43]=[C:18]([C:16]#[N:17])[CH:19]=[CH:20][C:21]=2[O:26][C:25]([CH3:27])([CH3:28])[C@@H:24]1[OH:29]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Product: COC(CN[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O)OC
Yield: 90 %

Procedure:
A mixture of (1aR-cis)-1a,7b-dihydro-2,2-dimethyl-2H-oxireno-[c][1]benzopyran-6-carbonitrile (750 mg, 3.73 mmol, the title A compound of Example 3), dimethyl aminoacetal (1.2 mL) was heated in a sealed tube at 75° C. for two days. The reaction mixture was purified by flash column chromatography (ethyl acetate and hexane, 1:1) to give a colorless oil (1.0 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:22](=[O:23])[C:13]3=[CH:14][NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:22](=[O:23])[C:13]3=[CH:14][NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1

Procedure:
The solution of 1.9 g of 2-(p-nitrophenyl)-pyrazolo-[4,3-c]-quinolin-3(5H)-one in the mixture of 18.6 ml of 2 N aqueous sodium hydroxide and 75 ml of ethanol is hydrogenated over 0.2 g of platinum oxide at 2.7 atm. for 6 hours. The mixture is filtered, the filtrate evaporated, the residue taken up in water and the solution washed with diethyl ether. The pH thereof is adjusted to about 8.5 by addition of aqueous ammonium chloride, the precipitate collected, washed successively with methanol and diethyl ether and dried, to yield the 2-(p-aminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing IR-peaks at 896, 885, 865, 840, 820, 815, 782, 776, 761, 740, 736 and 720 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[CH:2].[C:11]([CH:15]([CH2:18][SH:19])[CH2:16][SH:17])([CH3:14])([CH3:13])[CH3:12].CN(C)C=O.S(OC)(OC)(=O)=O>C(Cl)Cl.C(N(CC)CC)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[S:19][CH2:18][CH:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:16][S:17]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: CC(C)(C)C(CS)CS
Reactant: C#Cc1ccc(C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: COS(=O)(=O)OC
Product: C#Cc1ccc(C2SCC(C(C)(C)C)CS2)cc1

Procedure:
A mixture of 4-ethynylbenzaldehyde (131 mg., 1.00 mmol.), 2-t-butylpropane-1,3-dithiol (206 mg., 1.25 mmole) (E. L. Eliel and R. O. Hutchins (J. Amer. Chem. Soc. 1969, 91, 2703)) and the adduct of N,N-dimethylformamide and dimethyl sulphate (300 mg., 1.50 mmole) diluted with methylene chloride (2.0 ml.) was maintained at 23° for 48 hours. After cooling to 0°, triethylamine (0.2 ml) was added, and the solution was washed with water (3×2 ml.) which was again extracted with methylene chloride. The combined organic layers were dried (anhydrous magnesium sulphate) and evaporated to give a residue (320 mg.) which was recrystallized from hexane (2.5 ml.) to give 2-(4-ethynylphenyl)-5-t-butyl-1,3-dithiane, m.p. 149°, (120 mg , 43%)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>CN(C)C=O>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([CH2:19][CH3:20])[CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][NH:2][CH2:33][C:32]2[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=2)[CH:5]=1)[CH3:18]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a solution of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-ethylpropanoate hydrochloride (203 mg, 0.673 mmol) in N,N-dimethylformamide (4 mL), potassium carbonate (232 mg, 1.68 mmol) and 4-(trifluoromethyl)benzyl bromide (169 mg, 0.707 mmol) were added, and then the mixture was stirred for 3 hours at room temperature and for 4 hours under heating at 60° C. After cooling, the mixture was poured in ice water, which was extracted with diethyl ether. The organic later was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=2:1 v/v) to afford 92.3 mg (32%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:34][S:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)(=[O:37])=[O:36]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:42][C:41]2[CH:40]=[CH:39][C:38]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:45][CH:44]=2)[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((6.8 g, 33.5 mmol) in dry DMF (150 ml) under an inert atmosphere of Argon is treated with BEMP (10.5 ml, 36.5 mmol) dropwise, over two minutes. The solution is stirred at room temperature for 1 hour and then a solution of 4-methylsulphonyl benzyl bromide (10.0 g, 40.2 mmol) in DMF (60 ml) is added dropwise over 5 minutes. After stirring at room temperature overnight, the solvent is removed in vacuo and azeotroped with toluene (200 ml). The resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (20-100% ethyl acetate) to yield the titled compound as a green oil. (MH+ 373)
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([CH:22]([OH:25])[CH2:23][CH3:24])[CH:17]=[CH:16][N:15]=1>ClCCl>[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([C:22](=[O:25])[CH2:23][CH3:24])[CH:17]=[CH:16][N:15]=1
Reactant: CCC(O)c1ccnc(OC)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)c1ccnc(OC)c1OC

Procedure:
Celite (27 g, oven dried) and pyridinium chlorochromate (26.46 g; 12.27 mmol) were added to a solution of 2,3-dimethoxy-4-(1′-hydroxypropyl)pyridine (4) (18.6 g; 94.4 mmol) in anhydrous dichloromethane (300 mL). The resultant mixture was stirred at room temperature for 16 hours. The mixture was then filtered through a pad of Celite and silica gel. Concentration generated 13.8 g of the crude 1-(2,3-dimethoxy-pyridin-4-yl)-propan-1-one (5) product which was utilized in the subsequent synthesis step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[CH2:45][CH2:44][N:43]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 67.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (644 mg, 1.24 mmol, 68%) was obtained.
Reaction SMILES: Br[CH2:2][O:3][CH3:4].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16]=[O:17])[CH:10]=[CH:9]2.[H-].[Na+].O>C(COC)OC.C(OC(=O)C)C>[CH3:4][O:3][CH2:2][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH:16]=[O:17])[CH:10]=[CH:9]2
Reactant: COCBr
Reactant: O=Cc1ccc2cc(O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COCOc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromomethyl-methylether (1.50 mL, 18.3 mmol) was added dropwise to a stirred suspension of 6-hydroxy-2-naphthaldehyde (2.1 g, 12.2 mmol) and sodium hydride (0.73 g, 18.3 mmol) in dimethoxyethane at 0° C. The mixture was stirred for 1 h at room temperature. After the complete addition water was carefully added and it was entracte with ethylacetate (3×), dried over MgSO4 and concentrated in vacuo; yellow solid; yield: 2.64 g (91%);
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])C(O)=O)#[N:2].O>CC(N(C)C)=O>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[CH2:7][CH2:3][C:1]#[N:2]
Reactant: N#CC(Cc1c(Cl)cccc1Cl)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#CCCc1c(Cl)cccc1Cl
Temperature: 150 °C
Yield: 93.7 %

Procedure:
2-Cyano-3-(2,6-dichlorophenyl)propanoic acid (447 mmol, 109 g) was dissolved in DMA (179 ml) and heated for 2 hours at 150° C. After cooling, the reaction mixture was poured into water and extracted with ether. The organic layer was washed with a saturated solution of sodium hydrogen carbonate and then with a saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford 3-(2,6-dichlorophenyl)propanenitrile (94% yield, 83.8 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:4])[C:5]4[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=4)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamid, and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a yellow solid; mp 205-218° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.30 (m, 2H), 1.70-1.90 (m, 2H), 2.50-3.00 (m, 5H), 2.89 (s, 3H), 3.62 (s, 3H), 3.65 (s, 3H), 3.65-3.85 (m 2H), 4.40-4.50 (m, 1H), 6.50-7.10 (m, 8H), 7.45 (d, 2H), 9.11 (s, 1H); MS (ES) m/z: 621.0 (MH+); HRMS Calcd. for C28H37N4O8S2 (MH+): 621.2053. Found: 621.2058.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[O:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:18]([O:23][C:24]3[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=3)=[N:19][CH:20]=[N:21][CH:22]=2)[CH2:13][CH2:12]1>C(O)(C)C>[O:11]1[CH2:12][CH2:13][CH:14]([C:17]2[C:18]([O:23][C:24]3[CH:30]=[CH:29][C:27]([NH:28][C:2]4[S:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:26][CH:25]=3)=[N:19][CH:20]=[N:21][CH:22]=2)[CH2:15][CH2:16]1
Reactant: Nc1ccc(Oc2ncncc2C2CCOCC2)cc1
Reactant: Clc1nc2ccccc2s1
Solvent: CC(C)O
Product: c1ccc2sc(Nc3ccc(Oc4ncncc4C4CCOCC4)cc3)nc2c1

Procedure:
To a microwave vial was added 2-chlorobenzo[d]thiazole (68.5 μL, 0.553 mmol) and 4-(5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yloxy)aniline (150 mg, 0.553 mmol) with isopropanol (1.1 mL). The reaction was irradiated at 120° C. for 3 h with microwave irradiation. The crude reaction was concentrated under reduced pressure. Preparative HPLC afforded the target compound as a salt. The material was washed with sat. aq. sodium bicarbonate and extracted with dichloromethane before concentrating the combined organics under reduced pressure to a pale yellow oil. MS (ESI, pos. ion) m/z: 405.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:29])[N:17]([C@@H:19]([CH2:27][OH:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.C(O)(=O)C>ClCCl>[C:11]([O:15][C:16](=[O:29])[N:17]([C@@H:19]([CH:27]=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:18])([CH3:12])([CH3:14])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@@H](C=O)Cc1ccccc1
Temperature: -63 °C
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (4.24 mL, 48.61 mmol) was dissolved in dichloromethane (30 mL). The solution was cooled to −63° C. A solution of DMSO (4.6 mL, 64.81 mmol) in dichloromethane (20 mL) was added dropwise. The solution was stirred for 5 min and a solution of N-((1R)-1-(hydroxymethyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester (8.6 g, 32.41 mmol) in dichloromethane (200 mL) was added dropwise over a period of 30 min. The reaction mixture was stirred for 20 min at −63° C. A solution of triethylamine (18.07 mL, 129.62 mmol) in dichloromethane (40 mL) was added over a period of 25 min. The solution was warmed to −35° C. and immediately cooled to −63° C. It was stirred at this temp. for 1 h. Acetic acid (8.15 mL, 142.58 mmol) was added. The reaction mixture was warmed to 10° C. and washed with water (2×200 mL) and satd. sodium hydrogencarbonate solution (150 mL). The org. phase was dried over magnesium sulfate. The solvent was removed in vacuo to give 7.536 of N-((1R)-1-formyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]([O:21][CH3:22])[C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[O:23]1[CH2:26][C:25](=O)[CH2:24]1.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:22][O:21][CH:4]([O:3][CH3:2])[C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][C:6]=1[CH:15]1[CH2:16][CH2:17][N:18]([CH:25]2[CH2:26][O:23][CH2:24]2)[CH2:19][CH2:20]1
Reactant: O=C1COC1
Reactant: COC(OC)c1nc2c(cc1C1CCNCC1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: COC(OC)c1nc2c(cc1C1CCN(C3COC3)CC1)CCCN2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-(dimethoxymethyl)-6-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride (Intermediate 342, 0.94 g, 2.294 mmol), 3-oxetanone (0.777 g, 10.78 mmol) and Et3N (0.96 ml, 6.88 mmol) in 1,2-dichloroethane (50 ml) was cooled to 0° C., treated with sodium triacetoxyborohydride (1.54 g, 6.88 mmol) and then slowly warmed to room temperature. After 1.5 h, the reaction mixture was poured into H2O and evaporated to dryness. The crude material was purified by reverse phase chromatography (Reprosil C18/250×30 mm/5 um, 0.1% TFA in H2O/acetonitrile 70:30 to 5:95). The product-containing fractions were treated with NaHCO3 and then concentrated to dryness. The residue was suspended in MeOH, stirred for 1 h and filtered, washing with additional MeOH. The filtrate was evaporated to give the title compound as a yellow solid. (UPLC-MS 3) tR 0.34 min; ESI-MS 348.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:18][CH:19]([NH2:21])[CH3:20].O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:19]([CH3:20])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: CC(C)N
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)Nc1nc(Cl)nc2c1CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (172 mg, 0.65 mmol) in NMP (2 mL) was added propan-2-amine (115 mg, 1.95 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out, air-dried, and purified via Biotage (12 g, hexanes-70% EtOAc) to give 2-chloro-N-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (154 mg, 0.535 mmol, 82% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.30 (2H, t, J=7.5 Hz), 7.20-7.25 (1H, m), 7.15 (1H, d, J=1.5 Hz), 7.13 (1H, s), 4.53 (1H, d, J=7.3 Hz), 4.37-4.45 (1H, m), 4.23-4.28 (1H, m), 2.58-2.78 (3H, m), 2.10-2.17 (1H, m), 1.27-1.29 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N:10]1[C:15]2[NH:16][CH:17]=[CH:18][C:14]=2[C:13]([C:19]2[C:20]([NH:25][C:26]3[C:27]4[CH:28]=[CH:29][N:30]=[C:31](Cl)[C:32]=4[CH:33]=[CH:34][C:35]=3[CH3:36])=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:12][CH:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:10]1[C:15]2[NH:16][CH:17]=[CH:18][C:14]=2[C:13]([C:19]2[C:20]([NH:25][C:26]3[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]4[C:27]=3[CH:28]=[CH:29][N:30]=[C:31]4[NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:12][CH:11]=1
Reactant: Cc1ccc2c(Cl)nccc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Temperature: 120 °C

Procedure:
A mixture of 4-aminobenzonitrile (35 mg, 299 mmol), N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine (110 mg, 284 μmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 11 μmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg, 23 μmol) were suspended in THF (1 mL) and sealed. The mixture was sonicated until homogeneously mixed. Lithium bis(trimethylsilyl)amide (1.28 mL, 1280 mmol) was then added through a syringe, then mixed well with sonication. The reaction tube was heated via microwave to 120° C. for 15 min. The reaction mixture was cooled to room temperature, then partitioned between EtOAc (3×50 mL) and NaHCO3 (aq., sat). The organic layer was washed with brine, and extracted with HCl (aq., 1 N, 3×50 mL). The aqueous layers were combined and filtered through a layer of celite. The filter cake was rinsed with 1 N HCl. The filtrate was then cooled in ice and neutralized with NH4OH (aq., conc.) to pH 8, then extracted with EtOAc (4×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and then concentrated to give a brown solid which was then triturated with MeOH to give a light brown solid upon filtration. The filter cake was air dried over the weekend to give 4-(5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile. MS (ESI, pos. ion) m/z: 469.2