Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: Nc1ccccc1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A flask with a stirrer was charged with 10.9 g of 2-aminophenol, 10.1 g of triethylamine and 100 ml of acetone, and a solution of 17.7 g of benzenesulfonyl chloride in 50 ml of acetone was dropwise added with cooling with ice over 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethyl acetate/n-hexane mixed solvents, to give 11.0 g of an end product. Melting point 140.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.C([O:26][CH2:27][CH3:28])(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([N:19]4[C:9](=[O:10])[C:8]5[C:28](=[CH:2][CH:3]=[CH:4][CH:5]=5)[C:27]4=[O:26])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Reactant: CCOC(C)=O
Product: Cc1c(C)c(N2C(=O)c3ccccc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(F)cc1
Yield: 72 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, the title compound was synthesized according to Reference Example 35a. Yield: 72%. Melting point: 209-211° C. (Ethyl acetate)
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[OH:14][C:15]1[C:20]2=[N:21][CH:22]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24](=[O:25])[N:19]2[CH:18]=[CH:17][CH:16]=1.P([O-])([O-])(O)=O.[K+].[K+].Br>C(O)(=O)C.CC(CC)=O>[BrH:1].[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:14][C:15]1[C:20]2=[N:21][CH:22]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24](=[O:25])[N:19]2[CH:18]=[CH:17][CH:16]=1)([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: CCOC(=O)c1cnc2c(O)cccn2c1=O
Agent: Br
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccccc1COc1cccn2c(=O)c(C(=O)OCC)cnc12

Procedure:
To a solution of 5.0 g of ethyl α-bromo-o-toluate, 4.7 g of 9-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-3-carboxylic acid, ethyl ester, and 200 ml of ethyl methyl ketone is added 3.9 g of anhydrous dipotassium hydrogen phosphate and the mixture stired and heated under reflux for 18 hours. The cooled mixture is filtered, and the filtrate is concentrated in vacuo to give a semi-solid product. To this product, 3.9 g, in 10 ml of acetic acid is added a solution of 0.81 g of hydrogen bromide in 4 ml of glacial acetic acid, dropwise, with agitation. The crystalline product that separates is filtered, washed with anhydrous ether, and recrystallized from acetonitrile to give the named product.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:27]([NH:31][CH2:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH2:27]([N:31]([CH2:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: FC(F)(F)c1ccc(-c2cncc(Br)n2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 18.7 %

Procedure:
A mixture of 2-bromo-6-[4-(trifluoromethyl)phenyl]pyrazine (0.5 g, 1.6 mmol), N,N-diisopropylethylamine (0.29 mL, 1.6 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.5 g, 1.8 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature, and the residue dissolved in CH2Cl2 (130 mL), the organic extract was washed water (30 mL) passed through a hydrophobic frit and concentrated in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting 1:19–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (0.15 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)=[CH:19][N:18]=1>>[CH3:11][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:28][CH2:27][O:26][CH2:25]3)=[CH:19][N:18]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(OC2CCOC2)cn1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OC3CCOC3)cn2)cc1

Procedure:
N-[3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide was reacted with 2-chloro-5-(tetrahydrofuran-3-yloxy)pyridine in analogy to example 2c.
Reaction SMILES: Cl.[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][OH:15])[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: OCCBr
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)C1CCN(CCO)CC1
Temperature: 60 °C
Yield: 66.3 %

Procedure:
A mixture of 4-(methylsulfonyl)piperidine hydrochloride (900 mg, 4.51 mmol), 2-bromoethanol (1126 mg, 9.01 mmol) and potassium carbonate (1869 mg, 13.52 mmol) in acetonitrile (4 mL) was heated up at 60° C. for 13 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the crude, the crude was purified by 0-35% ethyl acetate/methanol to provide the desired product as colorless oil (620 mg, 66%). LCMS: m/e 208.1 (M+H)+, 0.27 min (method 6).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5]2.[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28](B(O)O)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5]4)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)ccc21
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
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Yield: 211.1 %

Procedure:
A mixture of tert-butyl 5-bromo-1H-indazole-1-carboxylate (Intermediate 3) (1.07 g) {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 64) (0.85 g) sodium carbonate (1.9 g) and tetrakis(triphenylphosphine)palladium(0) (0.42 g) in 1,2-dimethoxyethane (70 ml) was stirred at reflux under nitrogen for 20 h. the solvent was removed and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was re-extracted with ethyl acetate (3×30 ml) and the combined organic extracts were dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (75:25 to 60:40) to give the title compound (3.1 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:10]1[C:4]2[C:3]3[C:11](=[O:12])[NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[S:20][C:2]=3[S:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Nc1ccccc1S)c1c(Br)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1Nc2ccccc2Sc2sc3c(c21)CCCC3

Procedure:
Alternatively, in the same manner as in Example 18 and using 2-bromo-4,5,6,7-tetrahydro-N-(2-mercaptophenyl)-benzo[b]thiophene-3-carboxamide, dimethyl sulfoxide and potassium carbonate, 1,2,3,4-tetrahydro[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one is obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.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.[Cu]I>[C:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(Br)nc1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
A mixture of 6-bromonicotinaldehyde (500 mg, 2.69 mmol), 1-dodecyne (680 mg, 4.09 mmol), triphenylphosphine (23 mg, 0.09 mmol), triethylamine (470 ml, 3.38 mmol) and bis(triphenylphosphine)palladium(II) chloride (94 mg, 0.13 mmol) in THF (10 mL) was stirred under argon at rt for 30 min. Copper(I) iodide (21 mg, 0.11 mmol) was added and the mixture was stirred for 21 hours at rt. The solvent was removed under reduced pressure. The residue was diluted with a saturated aqueous solution of NH4Cl (20 mL) and extracted with Et2O (50 ml+2×20 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduce pressure. The residue was purified by flash chromatography (c-Hex/EtOAc 4/1) to give the title compound as yellow oil (218 mg, 29%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 9.00 (s, 1H), 8.11 (d, 1H, J=8.1 Hz), 7.52 (d, 1H, J=8.1 Hz), 2.49 (t, 2H, J=7.1 Hz), 1.67 (m, 2H), 1.47 (m, 2H), 1.28 (m, 12H), 0.89 (t, 3H, J=6.8 Hz). M−(LC/MS(ESI)): 270.3; M+(LC/MS(ESI)): 272.4. HPLC (Condition A), Rt: 5.23 min (HPLC purity: 98.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[CH:7]=[O:8])[CH3:2]
Reactant: CC(C)I
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OC(C)C
Temperature: 45 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To 3-ethoxy-4-hydroxybenzaldehyde (20.0 g, 120 mmol) in dimethylformamide (250 mL) was added potassium carbonate (33.1 g, 240 mmol) then 2-iodopropane (18 mL, 180 mmol). The reaction mixture was heated to 45° C. and stirred for 3 h. After cooling to rt, the crude reaction mixture was extracted with ethyl acetate (3×). The combined extracts were then washed with water (3×) then brine and dried over sodium sulfate. The solvent was removed to give 24 g of 141A as a yellow oil. LC-MS: 231.17 (M+Na)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].C(O)C.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>C(Cl)(Cl)Cl>[CH2:16]([NH:23][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cccc(C(O)CNCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
In a 250 mL round-bottomed flask, 2-bromo-1-(3-methoxyphenyl)ethanone (3 g, 13.1 mmol) was combined in CHCl3 (55.0 ml) and ethanol (11.0 ml) to give a colorless solution. The solution was cooled to 0° C. Benzylamine (5.61 g, 5.72 ml, 52.4 mmol) was added. After stirring for 0.5 h at 0° C. and then 2 h at room temperature, LCMS indicated that the reaction was mostly complete. (M+H)+=256 m/e. The reaction was cooled again to 0° C. and NaBH4 (743 mg, 19.6 mmol) was added. The reaction was allowed to warm to room temperature and was stirred at this temperature for 2.5 h until reaction was complete. The reaction mixture was quenched with 1M HCl (25 mL) at 0° C. followed by stirring at room temperature for 1 h. The reaction mixture was poured into 150 mL 1 M NaOH and extracted with ethyl acetate (3×150 mL). Combined organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 100% ethyl acetate) to yield 2-Benzylamino-1-(3-methoxy-phenyl)-ethanol (1.95 g, 58%). (M+H)|=258 m/e.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][C:4]([OH:8])=[N:3]1.[CH2:9](Br)[C:10]#[CH:11].C(O)C>C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([S:7][CH2:11][C:10]#[CH:9])=[N:5][C:4]([OH:8])=[N:3]1
Reactant: Cn1nc(O)nc1S
Reactant: C#CCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: C#CCSc1nc(O)nn1C

Procedure:
13.1 g of 1-methyl-3-hydroxy-5-mercapto-1,2,4-triazole and 13.1 g of propargyl bromide are added to 100 ml of ethanol. To this suspension are added all at once 11.1 g of triethylamine. The exothermic reaction causes the temperature to rise to 45° C. After a short time a yellow product falls out of the clear solution and is filtered off and washed with water. The undissolved material is dried over P2O5.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH3:17])=[C:11]([N+:18]([O-])=O)[CH:10]=1)=[O:7])(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][CH2+:40]1SC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][C:40]1=[N:18][C:11]1[CH:10]=[C:9]([NH:8][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:7])[CH:14]=[CH:13][C:12]=1[NH:15][CH2:16][CH3:17])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCNc1ccc(NC(=O)COC(C)=O)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)COC(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-acetoxy-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.73 (1H, br s), 7.44-7.51 (3H, m), 7.23-7.34 (5H, m), 7.16 (1H, t), 7.08 (1H, dd), 7.00 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.67 (2H, s), 3.74 (3H, s), 2.98 (2H, q), 2.20 (3H, s), 1.00 (3H, t); MS(ESI): 588 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14]C)[C:6]2=[O:13].C([O-])(=[O:18])C.[Na+].CCOC(C)=O>C(O)(=O)C>[CH3:12][O:11][C:8]1[CH:7]=[C:3]([CH2:4][CH:5]([CH3:14])[C:6]([OH:13])=[O:18])[CH:2]=[CH:10][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: CCC1Cc2c(Br)ccc(OC)c2C1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc(CC(C)C(=O)O)c1
Yield: 73.5 %

Procedure:
A mixture of the indanone (5c, 29.7 g, 0.110 mol), sodium acetate (15.0 g, 0.183 mol), 10% palladium-coal (3.01 g) in acetic acid (300 ml) was hydrogenated at atmospheric pressure. The catalyst was filtered off and the solvent evaporated. The residue was partitioned between water and AcOEt and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with water, 5% NaHCO3 and brine, dried, filtered and evaporated. The crude product was purified by recrystallization from hexane:AcOEt to give the pure titled compound (15.7 g, 3 steps yield 51%), mp, 67-69° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:18]([CH3:22])[C:19](=O)[CH3:20]>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:15][C:18]([CH3:22])=[C:19]([CH3:20])[N:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)Cl
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Solvent: CO
Product: Cc1nc(C2CCN(Cc3ccccc3)CC2)oc1C

Procedure:
7 g 1-benzyl-piperidine-4-carboxylic acid amide and 13 mL 3-chlorobutan-2-on were stirred 6 h at 180° C. under microwave conditions. The mixture was diluted in methanol and n-methylpyridinone and purified by HPLC to give 1.48 g of the desired product.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)SC)#[N:5]>>[C:4]([NH:6][C:7]([NH:3][CH2:1][CH3:2])=[N:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:5]
Reactant: CCN
Reactant: CSC(=NCCSCc1cccnn1)NC#N
Product: CCNC(=NCCSCc1cccnn1)NC#N

Procedure:
Anhydrous ethylamine is reacted with N-cyano-N'-[2-(3-pyridazinylmethylthio)ethyl]-S-methylisothiourea by the procedure of Example 4 to give N-cyano-N'-ethyl-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [Br:1][CH:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].C1COCC1.B.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:1][CH:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CC(Br)CCCCCCCCC(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Br)CCCCCCCCCO
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A flask containing 10-bromoundecanoic acid (25.0 g, 94.2 mmol) was charged with dry THF (250 ml), immersed in an ice/water bath and fitted with an addition funnel. The addition funnel was charged with borane-THF solution (1.0M, 113 ml, 113 mmol) which was added to the stirred reaction mixture over a period of 45 minutes. 3 hrs after the addition was completed, the reaction was poured into a stirred mixture of EtOAc (500 ml) and 10% aqueous potassium carbonate (300 ml). After vigorously stirring for 0.5 hr, the layers were separated. The organic phase was washed with water (250 ml) and brine (250 ml), dried (Na2SO4), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:4; EtOAc:hexanes) provided 10-bromo-undecan-1-ol (20.8 g, 88%).
Reaction SMILES: [C@@H]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CS(C)=O>[CH2:20]([N:12]1[C:13]2[C:14](=[O:15])[NH:16][CH:17]=[N:18][C:19]=2[N:10]=[CH:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1[nH]cnc2ncn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.23 g of inosine was dissolved in 90 ml of dimethyl sulfoxide, and 16 ml of benzyl bromide was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was poured into 3 L of ethyl acetate. The resulting supernatant was removed and the precipitated oil was dissolved in 10% hydrochloric acid (135 ml). The solution was heated at 70° C. with stirring for 4 hours. The solution was cooled to room temperature, and then neutralized to pH 7 using a 5N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, and dried to give 12.748 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:51])[C:24](=[O:50])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)=[O:33])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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.O>[OH:21][C:18]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:11][C:2]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[NH:31][C:28]4[CH:27]=[CH:26][C:25]([C:24]([N:23]([CH3:51])[CH3:22])=[O:50])=[CH:30][CH:29]=4)=[CH:40][CH:39]=3)=[N:3]2)=[CH:8][CH:7]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1ccc2c(N3CCOCC3)nc(Cl)nc2c1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(C(C)(C)O)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 4.9 %

Procedure:
To a 50 mL round bottom flask, 2-(2-chloro-4-morpholino-quinazolin-7-yl) propan-2-ol (0.08 g, 0.00026 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (0.128 g, 0.000312 mol), cesium carbonate (0.169 g, 0.00052 mol), DMF (3 mL) and water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.009 g, 0.000013 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 5 h. To the cooled reaction mixture, water was added and extracted with ethyl acetate. The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 10% MeOH in chloroform. The compound was further purified by prep TLC using 10% MeOH in chloroform to obtain the title compound [0.007 g, 5%]. 1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.97 (s, 1H), 8.44 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.97 (d, J=8.8 Hz, 3H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 5.30 (s, 1H), 3.83 (brs, 4H), 3.81 (brs, 4H), 2.96 (s, 6H), 1.52 (s, 6H). LC-MS (ESI): Calculated mass: 554.2; Observed mass: 555.1 (RT: 0.17 min).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>CC(C)=O.C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (Compound 1a) (5.82 g; 30.0 mmol) in acetone (480 mL), cooled to 0° C., was added a solution of 4-methoxy-phenol (3.75 g; 30.0 mmol) in a mixture of 1 N NaHCO3(aq) (30 mL) and H2O (120 mL) dropwise by an addition funnel. After completion of addition, the reaction mixture was allowed to warm to ambient temperature, and was then stirred at room temperature for 3 h. The resultant mixture was evaporated in vacuo, and the residue was washed sequentially with EtOAc, 1 N NaOH(aq), and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude material. The crude material was recrystallized from Et2O-hexanes to afford Compound 1b (7.70 g; 91% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.13-7.15 (m, 2H), 6.98-7.01 (m, 2H), 3.87 (s, 3H); MS: m/z 282.0 (M+H)+.