Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:6]=1[C:21](=[O:23])[CH3:22].[C:24](=S)=[S:25].CI.[CH3:29][S:30]([CH3:32])=O>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:6]=1[C:21](=[O:23])[CH:22]=[C:29]([S:25][CH3:24])[S:30][CH3:32]
Reactant: S=C=S
Reactant: COc1ccc(COc2cccc(OC)c2C(C)=O)cc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccc(COc2cccc(OC)c2C(=O)C=C(SC)SC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 500 mL round bottom flask is charged with 95% NaH (7.28 g, 288 mmol) and dry DMSO is added (170 mL). To the resulting heterogeneous mixture is added dropwise, 1-[2-methoxy-6-(4-methoxybenzyloxy)phenyl]ethanone (41.2 g, 144 mmol) in dry DMSO (60 mL). The mixture is stirred at room temperature for 10 min, at which time carbon disulfide is added dropwise (8.69 mL, 144 mmol), followed immediately by methyl iodide (18.0 mL, 288 mmol). Heat and gas are evolved during the addition of both reagents prompting careful addition. The homogenous solution is stirred for 18 h at room temperature and then poured slowly into three volumes of water. The solid product is filtered and dried under high vacuum to give the title compound as an orange solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:80][C:81]1[CH:88]=[CH:87][C:84]([NH:85][CH3:86])=[CH:83][CH:82]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:80][C:81]1[CH:88]=[CH:87][C:84]([N:85]([CH3:86])[C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]2)=[O:13])=[CH:22][CH:21]=3)=[O:24])=[CH:83][CH:82]=1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CNc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1)c1ccc(F)cc1
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-fluoro-N-methylaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a yellow solid (44%).
Reaction SMILES: CC1S[C:5]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([OH:16])=O)=[CH:8]2)=NC=1.S(Cl)([Cl:19])=O.[C:21]1(C)C=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:13]=[C:12]1[N:7]([C:5]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:8]=[C:9]([C:14]([Cl:19])=[O:16])[CH:10]=[CH:11]1
Reactant: Cc1cnc(-n2cc(C(=O)O)ccc2=O)s1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1
Product: O=C(Cl)c1ccc(=O)n(-c2ccccc2)c1
Temperature: 100 °C

Procedure:
After 510 mg (2.15 mmol) of 1-(5-methyl-1,3-thiazole-2-yl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid obtained in Example 45-2 was dissolved in 10 mL of toluene, 522 mg (4.30 mmol) of thionylchloride was added to the solution. Afterward, the resulting reaction solution was stirred under reflux at about 100° C. for 2 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo. The resulting solid compound was used in Example 45-4 without an additional purification process.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:30]([CH:32]1[CH2:34][CH2:33]1)#[C-:31]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:31]([NH:30][CH:32]3[CH2:34][CH2:33]3)=[C:13]([C:12]3[CH:15]=[CH:16][CH:17]=[C:10]([Cl:9])[CH:11]=3)[N:8]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: [C-]#[N+]C1CC1
Reactant: O=Cc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Clc1cccc(-c2nc3ccc(Cl)cn3c2NC2CC2)c1
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
5-chloropyridin-2-amine (100 mg, 778 μmol, Eq: 1.00), 3-chlorobenzaldehyde (115 mg, 93.0 μl, 817 μmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (44.4 mg, 233 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 10 min. To this yellow solution was added dropwise isocyanocyclopropane (52.2 mg, 47.4 μL, 778 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. The solvent was removed and the dark red oil was purified twice by flash column chromatography (ethyl acetate in hexanes) to give the product as yellow solid (45 mg, 18.2%). LC/MS (acid polar): 318.1 [M+H]+; 1H-NMR (CDCl3): δ 8.50 (s, 1H), 8.21 (s, 1H), 8.14 (d, 1H), 7.58 (d, 1H), 7.49 (t, 1H), 7.38 (d, 1H), 7.28 (d, 1H), 5.44 (s, 1H), 2.70 (m, 1H), 0.46-0.39 (m, 4H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:14]3[CH:15]=[C:16]([C:21]4[NH:25][C:24]5[CH:26]=[C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]6)[CH:28]=[CH:29][C:23]=5[N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1ccc(NC2CC2)nn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1 H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The intermediate compound N-cyclopropyl-6-ethynylpyridazin-3-amine was made as for Example 1 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 7.38-7.41 (1 H, d, J=9.0 Hz), 6.96-6.99 (1 H, d, J=9.0 Hz), 5.99 (1 H, s), 3.25-3.27 (1 H, m), 2.57 (1 H, s), 0.87-0.89 (2 H, s), 0.61-0.63 (2 H, s).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:9]2[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[OH:4].Cl.[CH3:37][N:38]([CH2:40][CH2:41][SH:42])[CH3:39].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[CH:3]([CH:5]1[C:11](=[O:12])[N:10]2[CH:6]1[CH2:7][C:8]([S:42][CH2:41][CH2:40][N:38]([CH3:39])[CH3:37])=[C:9]2[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[OH:4]
Reactant: CN(C)CCS
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)CCSC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(O)C(F)(F)F)C2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (51 mg), 2-(N,N-dimethylamino)ethylmercaptan hydrochloride (14.2 mg), and triethylamine (14 ml) in anhydrous DMF (2 ml) is stirred at room temperature for 2 hours. The mixture is diluted with ethyl acetate (20 ml), washed with 5% sodium bicarbonate (2×5 ml), water (4×10 ml), and brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue is purified by chromatography on silica gel to yield benzyl 6-(2,2,2-trifluoro-1-hydroxyethyl)-3-(2-dimethylaminoethylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: O.Cl.[O:3]=[C:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CC(C)=O>[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5]1
Reactant: O=C1CCNCC1
Reactant: COC(=O)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCN1CCC(=O)CC1
Yield: 41.5 %

Procedure:
To a suspension of 4-oxopiperidine hydrochloride monohydrate (10.0 g, 65.1 mmol) and methyl 3-bromopropanoate (7.8 ml, 71.6 mmol) in acetone (100 ml) was added K2CO3 (9.9 g, 71.6 mmol) and Et3N (9.1 ml, 65.3 mmol). The mixture was refluxed for 24 hours. The solid was removed by filtration and the solvent was evaporated. The residue was partitioned between EtOAc and H2O. The organic extracts were combined and dried over Na2SO4. The solvent was evaporated to give the title compound (15.0 g, 27.0 mmol, 42%) as an oil. 1H NMR (300 MHz, CDCl3) δ 3.70 (s, 3H), 2.75-2.85 (mult, 6H), 2.52-2.57 (mult, 2H), 2.42-2.46 (mult, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[CH3:29][NH:30][CH3:31].C(O)C>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:30]([CH3:31])[CH3:29])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CNC
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and 2.0 M dimethylamine in ethanol (4.60 ml, 9.30 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-dimethylaminopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (308 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](Br)[CH:8]=[N:9][CH:10]=1)=[O:4].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)[CH:8]=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: COC(=O)c1cncc(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
Assay Found: C 60.61; H 3.93; N 10.78% C13H10N2O4 requires C 60.47; H 3.90; N 10.85%; from 3-bromo-5-pyridinecarboxylic acid methyl ester (1.00 g) and 3-nitrophenylboronic acid (785 mg) tetrakis(triphenylphosphine)palladium(0) (164 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1.C(N(CC)CC)C.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4]([NH:17][CH:18]2[CH2:19][CH2:20][N:21]([S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH2:22][CH2:23]2)[N:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1nc(NC2CCNCC2)ccc1C(=O)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1
Yield: 60.8 %

Procedure:
To a solution of [2-Amino-6-(piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone (19.2 mg, 0.0611 mmol, Example 9) in methylene chloride (1.5 mL) were added triethylamine (12.6 mg, 0.124 mmol, Aldrich) in methylene chloride (0.2 mL) and a solution of ethanesulfonyl chloride (8.66 mg, 0.066 mmol, Aldrich 99+%) in methylene chloride (0.2 mL) at room temperature. After ˜30 mins the reaction mixture was concentrated and purified by reversed phase HPLC as described in Example 11 to give [2-Amino-6-(1-ethanesulfonyl-piperidin-4-ylamino)-pyridin-3-yl]-(2-fluoro-phenyl)-methanone as a white solid (15.1 mg, 60 % yield). HRMS, observed: 407.1533, calcd for (M+H)+: 407.1548.
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:40][N:41]1[C@@H:45]([CH3:46])[C@@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:43][C:42]1=[O:53]>C1COCC1.O>[CH2:9]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([CH:25]=[CH:26][C:27]([N:43]2[C@H:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:45]([CH3:46])[N:41]([CH3:40])[C:42]2=[O:53])=[O:29])[CH2:23][CH2:24]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)NC(=O)N1C
Reactant: O=C(O)C=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2ccccc2)N(C(=O)C=CC2CCN(C(=O)OCc3ccccc3)CC2)C(=O)N1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (1.37 g) was added dropwise over 10 minutes to a solution of 3-(benzyloxycarbonylpiperidin-4-yl)propenoic acid (2.5 g) in THF (20 ml) and the mixture was stirred for 1.5 hours. Lithium bis(trimethylsilyl)amide (8.65 ml)was added to a solution of (4R,5S)-1,5dimethyl4-phenyl-2-imidazolidinone (1.64 g) in THF (20 ml) at −10° C. and the mixture was stirred at −10° C. for 10 minutes, allowed to warm to 0° C. and then cooled again to −10° C. The acid chloride solution (prepared above) was added dropwise and the mixture was allowed to warm to room temperature. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were dried, evaporated to dryness and the residue was chromatographed on a Bond-Elut column eluted with an ethyl acetate/isohexane mixture (1:1) to give the title compound, yield 3.6 g. NMR (DMSOd6): 0.6 (d, 3H) 0.95 (d, 1H) 1.2 (m, 2H) 1.55 (m, 2H) 2.4 (m, 1H) 2.3 (s, 3H) 2.8 (m, 2H) 3.95 (m, 3H) 5 (s, 2H) 5.3 (d, 1H) 6.9 (m, 1H) 7.1 (m, 2H) 7.2–7.4 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:8][NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.O.C(=O)(O)[O-].[K+]>CCOCC>[CH3:1][O:2][C:3]([C:5]1([CH2:8][N:9]([C:18]2[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C1(CNC2CCCC2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
To a solution of 4.88 g (0.0247 mole) of 1-cyclopentylaminomethyl-cyclopropanecarboxylic acid methyl ester and 4.48 g (0.0231 mole) of 2,4-dichloro-5-nitro-pyrimidine in 100 mL of ether was added 50 mL of water and 4.62 g (0.0462 mole) of potassium bicarbonate. The mixture was stirred at ambient temperature for 5 hours. The resulting two-layer mixture was separated and the aqueous layer was extracted with ether. The combined ether extracts were washed successively with aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 7.80 g of 1-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclopropanecarboxylic acid methyl ester (IV-53) as a yellow solid.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][CH2:22][C:23]([O:25]CC)=[O:24])=[N:6][CH:5]=1>C1COCC1.C(O)C.O>[Br:3][C:4]1[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[CH:11][CH:10]=2)[C:7]([S:21][CH2:22][C:23]([OH:25])=[O:24])=[N:6][CH:5]=1
Reactant: CCOC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Aqueous lithium hydroxide solution (1M, 44 mL, 44.00 mmol) was added to a solution of ethyl 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate (9.14 g, 21.96 mmol) in THF (60 mL), ethanol (24 mL) and water (20 mL), and stirred for 4 h. After concentrating, the residue was acidified with aqueous HCl solution (1N, 50 mL), diluted with water (100 mL) and filtered to afford 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetic acid as an off-white solid (8.52 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[O:16][CH3:17].O.[OH-].[Na+]>CO>[CH3:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:9][C:4]=1[C:3]([OH:18])=[O:2]
Reactant: COC(=O)c1cc(N2CCOCC2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(N2CCOCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (170 mg) was dissolved in MeOH (5 ml) and H2O (5 ml) and treated with 1 M aq. sodium hydroxide (2 ml). After stirring at r.t. for 16 h the mixture was concentrated and partitioned between EtOAc and H2O. the aqueous layer was acidified (pH 2.0) and then extracted further with EtOAc (×3). The combined organic fraction was washed with brine, dried (MgSO4) and reduced in vacuo to give 2-methoxy-5-morpholin-4-yl-benzoic acid (90 mg) as a yellow oil. (LC/MS (basic method): Rt 0.91 min., [M+H]+ 238).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](Cl)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[S-:17][C:18]#[N:19].[K+].C(OCC)C>CC(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([N:19]=[C:18]=[S:17])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(NC(N=C=S)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A solution of Example 41B (1.91 g, 6.31 mmol) in acetone (30 mL) at ambient temperature was treated with potassium thiocyanate (1.38 g, 14.1 mmol). The mixture was stirred for 6 hours and solids were removed by filtration. The filtrate was concentrated to provide a yellow residue. The residue was treated with diethyl ether, and the suspension was sonicated and filtered. Concentration of the residue and purification by recrystallization (25% ethyl acetate/hexanes) provided 1.85 mg of the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.O.[NH2:61][C:62]1[NH:66][N:65]=[N:64][N:63]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:61][C:62]3[N:63]=[N:64][NH:65][N:66]=3)=[O:28])=[CH:24][CH:23]=2)[C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Reactant: Nc1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nn[nH]n1)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
4-({(4-Chlorophenyl)-[4-(4-chlorophenyl)thiazol-2-yl]amino}methyl)benzoic acid (0.15 g, 0.33 mmol) was dissolved in DMF (5 mL) and 1-hydroxybenzotriazol (49 mg, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol), and triethylamine (51 μL, 0.36 mmol) were added and the resulting mixture was stirred at room temperature for 15 minutes. 5-Aminotetrazole hydrate (34 mg, 0.33 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. Water was added and the mixture was stirred at room temperature for 1 hour and filtered. Washing with water and drying in vacuo afforded 145 mg (84%) of the title compound as a solid.
Reaction SMILES: [I:1][C:2]1[C:3]([O:7][CH3:8])=[N:4][NH:5][CH:6]=1.CC1C=CC(S(O[CH:20]2[CH2:29][CH2:28][C:23]3([O:27][CH2:26][CH2:25][O:24]3)[CH2:22][CH2:21]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=N1>CN(C=O)C>[O:24]1[C:23]2([CH2:28][CH2:29][CH:20]([N:5]3[CH:6]=[C:2]([I:1])[C:3]([O:7][CH3:8])=[N:4]3)[CH2:21][CH2:22]2)[O:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: COc1n[nH]cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cn[nH]c1
Solvent: CN(C)C=O
Product: COc1nn(C2CCC3(CC2)OCCO3)cc1I
Temperature: 100 °C

Procedure:
A solution of 4-iodo-3-methoxy-1H-pyrazole (0.783 g, 3.50 mmol), 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (1.20 g, 3.84 mmol), and Cs2CO3 (1.71 g, 5.24 mmol) in anhydrous degassed DMF (26.1 mL) was heated to 100° C. for 3 h. From LCMS, there was still starting material (pyrazole) therefore the reaction mixture was charged with an additional 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (0.437 g, 1.40 mmol) and Cs2CO3 (0.683 g, 2.10 mmol) and heated to 100° C. for an additional 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (25 mL) and separated. The aqueous was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (3×25 mL), brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in 1.29 g of a crude orange oil/solid mixture. The crude was crystallized from MeOH and the white crystals were filtered through a fritted funnel resulting in the title compound as white crystals. 1H NMR (400 MHz, CD3OD): δ=1.63-1.74 (m, 2H), 1.81-1.89 (m, 2H), 1.98-2.07 (m, 4H), 3.87 (s, 3H), 3.91-3.99 (m, 4H), 4.00-4.09 (m, 1H), 7.48 (s, 1H). MS (ES+): m/z 365.05 [MH+]. HPLC: tR=3.98 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[CH3:12].[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9]
Reactant: [H][H]
Reactant: COc1cccc([N+](=O)[O-])c1C
Agent: [Ni]
Solvent: CCO
Product: COc1cccc(N)c1C

Procedure:
200 gm (1.19 mols) of 2-methoxy-6-nitro-toluene were hydrogenated in 2.5 liters of ethanol in the presence of 25 gm of Raney nickel at 100 bar until the absorption of the calculated amount of hydrogen. The reaction mixture was filtered and evaporated in vacuo. After distillation 158.3 gm (97% of theory) of 3-methoxy-2-methylaniline were obtained.