Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]3([CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][NH:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:42]5[CH:43]=[N:44][NH:45][CH:46]=5)[CH:3]=4)[C:8]4([CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(-c3cn[nH]c3)cc21
Temperature: 140 °C

Procedure:
A stirred solution of 6′-bromo-1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (25 mg, 0.049 mmol), 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (9.60 mg, 0.049 mmol), PdCl2(PPh3)2 (3.5 mg, 4.95 μmol) and Na2CO3 (10.5 mg, 0.099 mmol) in toluene:water (2 mL:1 mL) was heated in the microwave for 2 h at 120° C. After this time PdCl2(PPh3)2 (5.0 mg) and 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (9.60 mg, 0.049 mmol) was added and the reaction was heated in the microwave for 1 h at 140° C. After this time the reaction was partitioned between EtOAc (50 mL) and water (20 mL). The separated organic layer was dried with MgSO4, filtered and evaporated in vacuo. Reverse phase HPLC (10 to 60% acetonitrile:water) gave 1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(1H-pyrazol-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. Mass Spectrum (ESI) m/e=493.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:18](Br)[CH2:19][CH3:20]>>[CH3:1][CH:2]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCCC(C)Oc1ccc(CO)cc1
Reactant: CCCBr
Product: CCCOCc1ccc(OC(C)CCCC(C)C)cc1

Procedure:
By the process described in Example 1, p-[(1,5-dimethyl-hexyl)-oxy]-benzyl alcohol is reacted with propyl bromide to give p-[(1,5-dimethyl-hexyl)-oxy]-α-propoxy-toluene (boiling point = 198°-200° C/1.0 mmHg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:22][CH:21]=1)#[N:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C#N)cc4)cc23)CC1
Yield: 43.3 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 38.0 mg (0.131 mMol) 4-cyanobenzoic acid, 13.5 mg (43.1%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:12][CH3:13])=[C:5]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=12.C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][N:23]=1)CCC>>[CH3:13][S:12][C:4]1[S:3][C:2]([C:19]2[O:20][CH:21]=[CH:22][N:23]=2)=[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:5]=12
Reactant: CSc1sc(Br)c2c1C(=O)CCC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Product: CSc1sc(-c2ncco2)c2c1C(=O)CCC2

Procedure:
In a similar way to that in Example 35, using 1-bromo-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one and 2-(tri-n-butylstannyl)oxazole, the title compound was isolated as a pale yellow solid (35 mg, 37%). mp 157-159° C. Found: C, 54.0; H, 3.7; N, 5.6%. C12H11NO2S2 requires: C, 54.32; H, 4.18; N, 5.28%. 1HNMR (250 MHz, CDCl3) δ 2.05-2.16 (2H, m), 2.56-2.61 (2H, m), 2.63 (3H, s), 3.20-3.25 (2H, m), 7.20 (1H, s), 7.66 (1H, s). MS (ES+) 266 (M+1).
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:7]([C:9]3[CH:10]=[C:11]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:29]=[CH:28][C:5]3[N:6]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:7]([C:9]4[CH:10]=[C:11]([C:20]([OH:23])([CH3:22])[CH3:21])[CH:12]=[CH:13][C:14]=4[N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:8][C:4]=3[CH:3]=2)=[CH:33][N:32]=1
Reactant: CC(C)(O)c1ccc(-n2cncn2)c(-c2nc3cc(Br)ccc3n2C(C)(C)C)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 110 °C
Yield: 69 %

Procedure:
To a sealed vial is added 2-[3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]propan-2-ol (60 mg, 0.13 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (35 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and 2M aqueous Na2CO3 (0.3 mL, 0.6 mmol). The reaction mixture is heated under Ar at 110° C. for 2 hours. The residue is diluted with EtOAc (20 mL), washed with brine (10 mL), dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-7% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (42 mg, 68%). LCMS (ESMS): m/z 469.50 (M++1)
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:22])([CH3:21])[CH2:6][C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH3:23]I>CN(C=O)C>[CH3:23][O:3][CH2:4][C:5]([CH3:22])([CH3:21])[CH2:6][C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a suspension of NaH (2.76 g, 69 mmol) in DMF (100 mL) was added dropwise a solution of (S)-tert-butyl 4-(3-hydroxy-2,2-dimethylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (6.6 g, 23 mmol) in DMF (150 mL). After the reaction mixture was stirring for 2 h, MeI (6.53 g, 46 mmol) was added dropwise. The mixture was quenched with NH4Cl (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. (S)-tert-butyl 4-(3-methoxy-2,2-dimethylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (6.4 g, 93%) was obtained as an oil that was used in the next step without further purification.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[C:30]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].O>ClCCl>[Br:22][C:23]1[CH:31]=[C:30]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:29]=[CH:28][C:24]=1[C:25]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:26]
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccn2)cc1Br
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Br)c1)c1ccccc1-c1ccccn1
Temperature: 25 °C
Yield: 104.8 %

Procedure:
To a stirred solution of the product from Reference Example 6, 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.54 g. 2.93 mmol) in dichloromethane (35 ml), under nitrogen, was added triethylamine (0.49 ml, 3.52 mmol). The mixture was cooled to 0° C. before a suspension of the crude 2-bromo-4-[(2-pyridin-2-ylbenzoyl)amino]benzoyl chloride (1.4 g) in dichloromethane (5 ml) was added dropwise. After the addition was complete, the reaction mixture was allowed to warm to room temperature. After 18 hours the reaction mixture was poured into water and sequentially washed with water, saturated aqueous sodium bicarbonate, twice with 10% aqueous acetic acid, once with saturated aqueous sodium bicarbonate and once with water. The organic solution was dried (Na2SO4), filtered and in vacuo to yield a dark purple foam (1.73 g). Purification by flash chromatography on silica gel with hexane-ethyl acetate (1:2) as the mobile phase, followed by concentration in vacuo, resulted in a colorless solid (1.23 g, 75%), m.p. 227.5°-229° C. MS (ESI),m/z: 563 (M+).
Reaction SMILES: [CH2:1]([C:3]1([C:12]2[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=2)[O:15][C:16]2[CH:23]=[C:22]([C:24]([C:26]3[N:27]([CH3:31])[CH:28]=[N:29][CH:30]=3)=[O:25])[CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])[CH3:2].[CH3:35][Mg+].[Br-]>C1COCC1>[CH2:1]([C:3]1([C:12]2[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=2)[O:15][C:16]2[CH:23]=[C:22]([C:24]([OH:25])([C:26]3[N:27]([CH3:31])[CH:28]=[N:29][CH:30]=3)[CH3:35])[CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])[CH3:2]
Reactant: C[Mg+]
Reactant: CCC1(c2cccc(Oc3cc(C(=O)c4cncn4C)ccc3C#N)c2)CCCCN(C)C1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC1(c2cccc(Oc3cc(C(C)(O)c4cncn4C)ccc3C#N)c2)CCCCN(C)C1=O
Temperature: 25 °C

Procedure:
2-[3-(3-Ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(3-methyl-3H-imidazole-4-carbonyl)-benzonitrile (Example 19) (0.216 g, 0.473 mmol) was dissolved in anhydrous THF (10 mL) and a 3.0 M solution of MeMgBr (1.10 mL, 3.30 mmol) was added and stirred at RT. The reaction was quenched with NH4Cl after 1 h, concentrated, diluted with EtOAc, washed with satd. NaHCO3 solution, water, brine, dried (MgSO4), concentrated and purified using SiO2 chromatography (1-3% MeOH/CH2Cl2 w/NH4OH) to give the title compound. FT/ICR MS (M+1)=473.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=3[O:17][CH3:18])[N:8]=2)[CH2:3][CH2:2]1.[CH3:19][O:20]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([C:4]2[NH:5][CH:6]=[C:7]([C:9]3[C:10]([O:17][CH3:18])=[CH:11][C:12]([O:15][CH3:16])=[C:13]([CH:14]=3)[CH:19]=[O:20])[N:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2c[nH]c(C3CC3)n2)c(OC)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cc(OC)c(-c2c[nH]c(C3CC3)n2)cc1C=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Ex-105B: To a solution of 2-cyclopropyl-4-(2,4-dimethoxy-phenyl)-1H-imidazole (0.51 g, 2.09 mmol) was added dichloromethyl methyl ether (0.28 mL, 3.13 mmol) followed by addition of titanium tetrachloride (1.0M in dichloromethane, 8.4 mL, 8.4 mmol) dropwise at 0° C. The solution was allowed to warm up to ambient temperature and stir for 4.5 hours. The reaction mixture was then poured into ice. The aqueous layer was adjusted to pH 12 and extracted with dichloromethane. The combined solution of dichloromethane was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated to afford 5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde which was used without further purification. 1H NMR (DMSO-d6) δ 13.95 (bs, 1H), 10.22 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 6.88 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 2.25 (m, 1H), 1.20 (m, 4H). MS m/z=245 ([M+H]+, 100%).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.N.C([O-])(=O)C.[NH4+].OC1C=CC=CN=1.P(Cl)(Cl)([Cl:25])=O>CN(C=O)C.C(O)C>[Cl:25][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnccc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: N
Agent: Oc1ccccn1
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1cnccc1Cl

Procedure:
Acetic acid ester i is converted to 3-oxo-butyronitrile ii by reaction with the anion of acetonitrile prepared by reaction of acetonitrile (CH3CN) with a strong base such as n-butyl lithium (n-BuLi) in a solvent such as THF. Reaction of oxo-butyronitrile ii with dimethylformamide-dimethyl acetal (DMF-DMA) in a solvent such as DMF at high temperature (e.g., 122° C.) results in the formation of bisdimethylaminomethylene intermediate iii which is converted to 4-hydroxy-nicotinonitrile iv by reaction with ammonia (NH3) or ammonium acetate (NH4OAc) in a solvent such as ethanol at reflux. Reaction of the hydroxypyridine with refluxing phosphorous oxychloride (POCl3) with or without catalytic DMF for 2 to 6 hours results in conversion to 4-chloro-nicotinonitrile v.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH3:32][N:33]1[C:37]([CH:38]=O)=[CH:36][N:35]=[CH:34]1>>[CH3:32][N:33]1[C:37]([CH2:38][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:36][N:35]=[CH:34]1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: Cn1cncc1C=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCc4cncn4C)ncn3)cccc2s1

Procedure:
N-(4-(6-(2-Amino-4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (prepared as described in WO04014871) was reacted with 1-methyl-1H-imidazole-5-carbaldehyde (Acros) under the conditions of Example 54 to give the title compound. MS (ESI, pos. ion) m/z: 540 (M+1). Mp: 263.0-265.2° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)c1ccc(C(=O)OC)c2[nH]c(=O)n(C)c12
Solvent: Cc1ccccc1
Product: CCC(CC)c1ccc(C(=O)OC)c2nc(Cl)n(C)c12
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of methyl 7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (1.30 g, 4.70 mmol) and phosphoryl chloride (10 ml) was heated at 100° C. for 3 h. The mixture was diluted with toluene and concentrated in vacuo to remove excess reagent. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on column silica gel with a 10% ethyl acetate/n-hexane to give 1.18 g (4.00 mmol, 85%) of the title compound as a colorless oil.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:12])([O-:11])[O-:10])=[C:5]([CH:13](Br)[CH3:14])[C:4]=1CC)C.Cl[C:19]1C=CC=C[C:20]=1Cl>>[CH2:19]([O:10][P:9]1(=[O:12])[C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=2[CH:13]([CH3:14])[O:11]1)[CH3:20]
Reactant: Clc1ccccc1Cl
Reactant: CCc1ccc(P(=O)([O-])[O-])c(C(C)Br)c1CC
Product: CCOP1(=O)OC(C)c2ccccc21
Yield: 55 %

Procedure:
A mixture of diethyl-2-(1-bromoethyl)phenylphosphonate (12 g, 0.037 mole) in 25 ml. of 1,2-dichlorobenzene was refluxed for 2 hours. The reaction mixture was vacuum distilled to yield 1-ethoxy-3-methyl-1,3-dihydro-2,1-benzoxaphosphole-1-oxide (4.3 g, 55% yield) as a colorless oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1.C([N:22](CC)C(C)C)(C)C>C(O)(C)C>[Cl:8][C:9]1[NH:10][C:11]([NH2:22])=[C:12]2[C:16]([N:17]=1)=[N:15][CH:14]=[N:13]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1[nH]c(Cl)nc2ncnc1-2
Temperature: 100 °C
Reaction time: 17 h
Yield: 70 %

Procedure:
A glass tube was charged with the above amount of TFA salt 13, commercially available 2,6-dichloropurine (1.02 g, 5.43 mmol), N, N-diisopropylethylamine (DIPEA, 3.14 mL, 4.96 mmol) and isopropyl alcohol (IPA, 6 mL). The glass tube was sealed and then shaken at 100° C. for 17 hours. The volatiles were evaporated and the resulting residue was purified by flash chromatography eluting with ethyl acetate-methanol (100:5, including 1% triethylamine) to afford 1.25 g of mono-SNA, product 14, racemic-(2-exo,3-exo-)-N6-[3-(dimethylamino)carbonylbicyclo-[2.2.1]hept-5-en-2-yl)]-2-chloro-1H-purine-6-amine, in 70% yield. 1H NMR (300 MHz, CD3OD) δ: 8.05 (s, 1H), 6.35 (m, 2H), 4.68 (m, 1H), 3.00 (s, 1H), 3.04 (s, 1H), 3.00 (s, 3H), 2.95 (s, 1H), 2.83 (s, 1H), 2.68 (s, 3H), 2.39 (d, J=8.7 Hz, 1H), 1.69 (d, J=9.0 Hz, 1H), 1,33 (m, 1H); LC-MS: purity: 90.51%; MS (m/e): 333.43 (M+H)+.
Reaction SMILES: CN1C=NN=C1S(CC1C=CC(C(O)=O)=CC=1)=O.[CH3:19][N:20]1[CH:24]=[N:23][N:22]=[C:21]1[S:25]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=1)(=[O:27])=[O:26].[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>>[Cl:38][C:39]1[CH:45]=[CH:44][C:42]([NH:43][C:33](=[O:35])[C:32]2[CH:31]=[CH:30][C:29]([CH2:28][S:25]([C:21]3[N:20]([CH3:19])[CH:24]=[N:23][N:22]=3)(=[O:26])=[O:27])=[CH:37][CH:36]=2)=[CH:41][C:40]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1
Reactant: Cn1cnnc1S(=O)(=O)Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: Cn1cnnc1S(=O)Cc1ccc(C(=O)O)cc1
Product: Cn1cnnc1S(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
114 mg of the mixture of 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was separated on reverse phase HPLC to give N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].N12CCN(CC1)CC2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][C:23](=[S:24])[N:22]([CH3:26])[CH3:21]
Reactant: CN(C)C(=S)Cl
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=S)Oc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
A solution of 2,6-dichloro-4-nitro-phenol (3.0 g, 14.4 mmol) in N,N-dimethylformamide (70 mL) at 25° C. was treated with 1,4-diazabicyclo[2.2.2]octane (3.16 mL, 28.8 mmol) and dimethylthiocarbamoyl chloride (2.85 g, 23.04 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with ethyl acetate (250 mL) and was then washed with a 1N aqueous hydrochloric acid solution (1×125 mL), water (1×125 mL), and a saturated aqueous sodium chloride solution (1×125 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80:20 petroleum ether/ethyl acetate) afforded dimethyl-thiocarbamic acid O-(2,6-dichloro-4-nitro-phenyl)ester (79) (3.2 g, 75%) as a white solid; EL-LRMS for C9H8Cl2N2O3S (M−Cl)+ at m/z=259. Exact Mass=293.9633; Molecular weight=295.15
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCCNC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCCN(C(=O)COC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-3-ylamide (example A180) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
With cooling in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (630 mg, 3.29 mmol) was added to 15 ml of methylene chloride solution containing o-anisidine (368 mg, 2.99 mmol) and 4-nitrobenzoic acid (500 mg, 2.99 mmol). After 1 hour of stirring at the same temperature, the reaction mixture was roughly adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, extracted with methylene chloride and then washed with water and saturated brine in that order. After drying on anhydrous magnesium sulfate, the solvent was removed by evaporation, and the resulting solid material was purified by silica gel column chromatography (methylene chloride) to obtain 712 mg (87.4%) of the title compound in the form of yellow powder.