Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]#[N:13])[CH:3]=1.C(N)(=[S:16])C.O>CN(C)C=O.O1CCOCC1.Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12](=[S:16])[NH2:13])[CH:3]=1
Reactant: CC(N)=S
Reactant: N#Cc1cc(Br)c2ccccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=S)c1cc(Br)c2ccccc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 4-bromonaphthalene-2-carbonitrile (0.57 g) in N,N-dimethylformamide (4 mL) and 4 mol/L HCl 1,4-dioxane solution (4 mL) was added thioacetamide (1.1 g) at room temperature, and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel to give 4-bromonaphthalene-2-carbothioamide (0.48 g). To a suspension of this compound (0.48 g) in ethanol (6 mL) was added ethyl 2-chloro-acetoacetate (0.59 g), and the mixture was stirred at 65° C. for 24 hours. After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried to give the title compound (0.41 g).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][N:10]2[C:22]3[CH:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:19]=[C:18]([OH:33])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:34](=[O:36])[NH2:35])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[C:3]1([CH2:9][N:10]2[C:22]3[CH:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:19]=[C:18]([O:33][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:34](=[O:36])[NH2:35])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(-c2ccc(C(F)(F)F)cc2)cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.12 h
Yield: 84 %

Procedure:
60% Sodium hydride in mineral oil (22 mg, 0.54 mM) was added to a solution of the 9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-4-hydroxy-5-carbamoyl carbazole (0.20 g, 0.43 mM) in 15 mL DMF and 3 ml THF. After 7 minutes, methyl bromoacetate (56 μl, 0.59 mM) was added and the resultant mixture stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.19 g (84%) of the {9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester. 1H NMR (DMSO-d6) δ8.0 (d, J=8 Hz, 2H), 7.85 (d, J=8 Hz, 2H), 7.7 (s, 1H), 7.6 (d, J=8 Hz, 1H), 7.6 (bs, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.3-7.1 (m, 6H), 7.1 (d, J=8 Hz, 1H), 7.0 (s, 1H), 5.8 (s, 2H), 5.1 (s, 2H), 3.7 (s, 3H). MS (FD) m/e 516,533.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[O:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].CN(C)C(N(C)C)=N>O1CCCC1>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[C:18](=[O:20])[CH2:19][O:15][C:16]2=[O:21])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: O=C1COC(=O)N1
Reactant: BrCCCCn1ccc2ccccc21
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: O=C1COC(=O)N1CCCCn1ccc2ccccc21

Procedure:
A solution of 3 g (11.90 mmol) of 1-(4-bromobutyl)-1H-indole, prepared in stage 2.1., of 2.41 g (23.80 mmol) of 1,3-oxazolidin-2,4-dione (J. Med. Chem., 1991, 34, 1538-1544) and of 2.74 g (23.80 mmol) of 1,1,3,3-tetramethylguanidine in 30 ml of tetrahydrofuran is brought to reflux for 14 hours under an inert atmosphere.
Reaction SMILES: N1CCCCC1.CN(C=O)C.[NH:12](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:13]([C:35]([OH:37])=[O:36])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:34])[NH:19]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O.CC(N=C=NC(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:12][C@H:13]([C:35]([OH:37])=[O:36])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:34]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c1C
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: N=C(N)NCCC[C@H](N)C(=O)O

Procedure:
After removing the Fmoc groups of the DMBHA resin prepared in (1) with 20% piperidine/DMF, 2.5 eq of Fmoc-Arg(Mtr)-OH based on the DMBHA resin was added, and condensation reaction was carried out in DMF according to the DIPCDI-HOBt method.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:14][NH2:15])=[N:10][CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:16](OC(OCC)OCC)(=O)C>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[N:10]([CH:16]=[N:15][N:14]=3)[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NNc1ncncc1-c1ccc(Cl)cc1
Reactant: CCOC(OCC)OC(C)=O
Solvent: CCCCCC
Product: Clc1ccc(-c2cncn3cnnc23)cc1
Reaction time: 0.38 h

Procedure:
A mixture of 2.0 g. of 5-(4-chlorophenyl)-4-hydrazinopyrimidine is shaken with 10 ml. of diethoxymethyl acetate. The mixture is allowed to stand 15-30 minutes and then is diluted with hexane. The precipitated product (1.81 g: 83%) is collected and recrystallized from ethanol to give the title compound; m.p. 193°-195° C .
Reaction SMILES: CO.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]2=[O:28])[CH2:6][CH2:5]1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13](=[O:28])[N:12]2[CH2:11][CH2:10][N:7]2[CH2:8][CH2:9][CH:4]([NH:3][CH2:39][C:30]3[CH:31]=[CH:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:29]=3)[CH2:5][CH2:6]2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4ccccc4c3)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 119.6 %

Procedure:
To 4 mL of a methanol solution containing 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide, 55 mg of 2-naphthoaldehyde and 40 μL of acetic acid were added, and stirred at room temperature for 80 min. To the reaction mixture, 52 mg of sodium cyanoborohydride was added, and stirred at the same temperature for 75 min. After the solvent was removed under reduced pressure, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=30:1], to give 0.21 g of 7-methoxy-N-methyl-1-(2-(4-((naphthalen-2-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxamide as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 25 °C
Reaction time: 7 h
Yield: 30.5 %

Procedure:
Sulfur trioxide-pyridine complex (1.71 g, 10.7 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (610 mg, 1.54 mmol), triethylamine (1.72 mL) in dimethyl sulfoxide (20 mL) at room temperature, and the mixture was stirred at room temperature for 7 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (185 mg, 0.469 mmol, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:10]=1[C:11]([N:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1)=[O:13]
Reactant: O=C(O)c1cnccc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 73 %

Procedure:
To a solution of 0.16 g (0.56 mmol) 4-(2,5-dichloro-phenoxy)-nicotinic acid in 3 mL N,N-dimethylformamide were added 0.225 g (0.59 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.29 mL (1.69 mmol) N,N-diisopropylethylamine. To the light yellow solution 0.07 mL (0.59 mmol) 1,2,3,4-tetrahydroquinoline (commercially available; CAS RN 635-46-1) was added and the resulting light yellow solution was stirred at room temperature for 23 hours. The reaction mixture was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50). The product-containing fractions were combined and evaporated to give 165 mg (73%) of the desired compound as a light brown solid. MS (ESI): m/z=399.06 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:18]C(=O)C)[CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[NH2:18][CH:14]([CH:15]([CH3:17])[CH3:16])[C:12]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1)=[O:13]
Reactant: CC(=O)NC(C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 88.6 %

Procedure:
The product of step (i) (1.57 g) was dissolved in dichloromethane (14 ml) and trifluoroacetic acid (4 ml) added. After 2 hours at room temperature the solvent was removed, ethyl acetate and 2N aqueous NaOH solution were added to give pH 8.0. The organic phase was separated and concentrated to give the sub-titled product as an oil (1.24 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=1[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([C:8]([NH:21][C:22]2[C:23]([C:24]([NH:26][CH:27]([CH3:28])[CH3:29])=[O:25])=[CH:30][CH:31]=[CH:32][C:33]=2[CH3:34])=[O:10])=[CH:6][N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Reactant: Cc1nc(C(F)(F)F)ncc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cnc(C(F)(F)F)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 0.8 g (4 mmol) of 4-methyl-2-trifluoromethylpyrimidine-5-carboxylic acid [made by the method of Palanki et al, J. Med. Chem. 2000, 43, 3995] stirring in 15 mL of methylene chloride, oxalyl chloride (2 mL, 23 mmol) was added. Upon addition of 2 drops of N,N-dimethylformamide, foaming and bubbling occurred. The reaction mixture was heated at reflux for 1 hr as a yellow solution. After cooling, the solvent was removed in vacuo and the resulting residue dissolved in 20 mL of tetrahydrofuran. To the stirred solution, 2-amino-3-methyl-N-(1-methylethyl)benzamide (1 g, 5 mmol) was added followed by the dropwise addition of N,N-diisopropylethylamine (3 ml, 17 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between ethyl acetate (200 mL) and 1N aqueous hydrochloric acid (75 mL). The separated organic layer was washed with water and brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid, which was suspended in a small amount of ethyl acetate and filtered to afford (after drying) 650 mg of the title compound, a compound of the present invention, melting at 248-251° C.
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=[C:21]([C:10]3[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:14][CH:15]=3)[C:29]=12
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(S(N)(=O)=O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 9.5 %

Procedure:
A solution of benzenesulfonamide-4-boronic acid pinacol ester (23 mg, 0.08 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA14 (2.2 mg, 10% yield). ESI-MS (M+H)+ m/z calcd 333.1, found 333.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][CH3:15])[CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26](=[O:27])[N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH3:15])=[CH:30][CH:31]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CCNCCN(CC)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CCN(CC)C(=O)OC(C)(C)C)C(=O)Oc1ccc(OC)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A solution of N-tert.-butoxycarbonyl-N,N'-diethylethylenediamine (3.22 g, 15 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) in tetrahydrofuran (100 mL) was added over 1 hour to a stirred, cooled solution of 4-methoxyphenyl chloroformate (2.78 g, 15 mmol) in tetrahydrofuran (50 mL). After stirring at 20°-25° overnight, solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue over silica gel and elution with 10-20% ethyl acetate-90-80% n-butylchloride gave 3.53 g of the carbamate as an oil.
Reaction SMILES: [F-].[Cs+].[CH:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)=[O:4].[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>COCCOC>[F:17][C:18]([F:20])([F:19])[CH:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)[OH:4]
Reactant: COC(=O)CCCc1ccc(C=O)s1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)CCCc1ccc(C(O)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.4 %

Procedure:
CsF (70 mg, 0.47 mmol) was added to a solution of methyl 4-(5-formylthiophen-2-yl)butanoate (1.0 g, 4.71 mmol) in dry 1,2-dimethoxyethane (5 MI) at 0° C., followed by trifluoromethyl trimethylsilane (0.8 MI, 5.65 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 h, quenched with 3N HCl, and stirred for further 30 min. The crude product was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether) to get methyl 4-(5-(2,2,2-trifluoro-1-hydroxyethyl)thiophen-2-yl)butanoate (0.63 g, yield 47%) as yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.02-7.01 (d, J=3.5 Hz, 1H), 6.74-6.73 (m, 1H), 5.23-5.17 (m, 1H), 3.68 (s, 3H), 2.88-2.84 (t, J=7.5 Hz, 2H), 2.81-2.80 (d, J=5.3 Hz, 1H), 2.40-2.36 (t, J=7.5 Hz, 2H), 2.05-1.97 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[Br:8][C:9]1[CH:10]=[N:11][N:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24](O[C@@H]4CCOC4)=[O:25])[CH2:20][CH2:19]3)=[N:14][C:13]=12>>[Br:8][C:9]1[CH:10]=[N:11][N:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:25])[CH2:20][CH2:19]3)=[N:14][C:13]=12
Reactant: O=C(O[C@@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Reactant: OC1CCOCC1
Product: O=C(OC1CCOCC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1

Procedure:
This was made by using tetrahydro-2H-pyran-4-ol and following the Part B in the procedure described above for making (R)-tetrahydrofuran-3-yl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[C:16]([CH3:17])[C:3]=12.[Br:18]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:18])=[C:16]([CH3:17])[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2scc(C)c2c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
To a stirred solution of ethyl 4-amino-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (210 mg, 0.839 mmol) (Description 30) in DCM (4 mL), was added N-bromosuccinimide (164 mg, 0.923 mmol) and the resulting mixture stirred for 20 min at RT. The mixture was concentrated and purified by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to afford the title compound (261 mg). LCMS (A) m/z: 329/331 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[C:7]2[C:16]3[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:24]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:46][C:9]1[C:8]2[N:24]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][C:29]3=[O:33])[C:7]=2[C:16]2[CH:15]=[C:14]([CH2:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2cnc3ccc(CCC(=O)N(C)C)cc3c2n1CCCN1CCCC1=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccc(CCC(=O)N(C)C)cc3c2n1CCCN1CCCC1=O
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3-{2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}-N,N-dimethylpropanamide, (0.66 g) in dichloromethane (75 mL) was added 3-chloroperoxybenzoic acid (60% pure, 423 mg, 1.62 mmol). After 18 hours concentrated ammonium hydroxide (50 mL) was added and the reaction was vigorously stirred for 10 minutes. p-Toluenesulfonyl chloride (311 mg, 1.62 mmol) was then added in one portion. The fractions were separated and aqueous fraction was extracted with chloroform (3×50 mL). The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-30% gradient of CMA in chloroform). The resulting product was washed with a 1% aqueous sodium carbonate and then recrystallized from acetonitrile to provide 75 mg of 3-{4-amino-2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}-N,N-dimethylpropanamide as an off-white solid, mp 184-186° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:21][CH2:22][CH2:23][CH3:24])=[N:8][C:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:10][CH:11]=1)=[O:5])C.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:22]([NH:21][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[N:8]=1)[CH2:23][CH3:24]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 110.5 %

Procedure:
A mixture of 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid ethyl ester (A2, 9.2 g), ethanol (115 mL), tetrahydrofuran (58 mL) and 2.0 mol/L aqueous sodium hydroxide (115 mL) was stirred at 40° C. for 4 hours, and then further stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, then 12 mol/L aqueous hydrochloric acid (19.5 mL) was added to the mixture (pH 5 to 6), and the organic solvent was evaporated under reduced pressure. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid (A3, 9.3 g) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17]OC4C=CC=CC=4)[CH:16]=[C:10]3[C:9]2=[O:25])=[N:6][CH:7]=1.B(Br)(Br)[Br:27]>C(Cl)Cl>[Br:27][CH2:17][C:15]1[CH:16]=[C:10]2[C:9](=[O:25])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH2:13][CH2:12][N:11]2[N:14]=1
Reactant: O=C1c2cc(COc3ccccc3)nn2CCN1c1ccc(F)cn1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: O=C1c2cc(CBr)nn2CCN1c1ccc(F)cn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-(5-fluoropyridin-2-yl)-2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100 mg, 0.296 mmol) was dissolved in DCM (2 mL), cooled to 0° C. and treated with 1M BBr3 in DCM (1.18 mmol, 1.18 mL). The reaction was allowed to warm to room temperature and stirred for 4 h. The reaction was diluted with DCM (5 mL) and then washed sequentially with 1M HCl (2 mL), saturated aq. NaHCO3 (2 mL) and 1N NaOH (2 ml). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give A (82 mg, 85%) as an oil: LC-MS (215 nm)>98%, 324.8 (M+H).