Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[N:8]=[N:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]
Reactant: CCSc1ccc(C(=O)O)nn1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A stirred mixture of 6-ethylsulfanyl-pyridazine-3-carboxylic acid (0.37 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-Aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 3 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-ethylsulfanyl-pyridazine-3-carboxylic acid [2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]amide as a white solid (0.76 g, 81% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.24 min (95.32%); mp: 160-162° C.; 1H NMR (DMSO-d6) δ 1.38 (t, J=7.3 Hz, 3H, CH3), 1.88 (s, 3H, CH3), 1.95-2.14 (m, 1H, CHH), 2.52-2.61 (m, 2H, CHH, CHH), 2.61-2.79 (m, 1H, CHH), 3.24-3.43 (m, 2H, CH2), 4.66 (d, J=6.2 Hz, 2H, CH2), 7.74-7.87 (m, 4H, Ar), 7.96 (d, J=8.9 Hz, 1H, Ar), 9.97 (t, J=6.2 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 12.67, 19.51, 22.51, 27.07, 27.60, 40.92, 57.25, 120.31, 121.67, 123.40, 125.41, 128.17, 129.87, 132.06, 145.52, 148.23, 161.45, 163.51, 166.22, 166.37, 170.65, 170.71; LCMS: MH=468; Anal Calcd for C22H21N5O5S+0.2H2O: C, 56.09; H, 4.58; N, 14.87. Found: C, 55.86; H, 4.59; N, 14.72.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(F)c2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(3,4-difluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BX) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; MS (ESI): 483.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[Br:12]Br>ClC(Cl)(Cl)Cl.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9][Br:12])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(C)cc(Br)cc1Br
Reactant: BrBr
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Br)cc(Br)cc1CBr
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A solution of the product of stage (b) (200 g) and benzyl peroxide (1 g) in tetrachloromethane (600 ml) was heated to reflux with stirring. Bromine (114 g) was added dropwise, and the mixture was stirred until it cooled to room temperature. Evaporation of the solvent gave an oil, distillation of which gave the title compound (183 g) as an oil, bp 115°-116° C./0.3 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[O:33])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(N)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(N)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 64.3 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0 mmol), K2CO3 (2.0 g) and 4-(3-bromopropoxy)-3-methoxybenzamide (2.32 g, 8.0 mmol) in acetonitrile (80 ml) was heated at reflux for 5 hours. At the end of the reaction the solvent was evaporated. The residue was extracted into dichloromethane. The inorganic insolubles were filtered off. The dichloromethane was concentrated again. The crude residue was purified by flash chromatography over a silica gel column (55 g, SiO2 ; eluted with 1% methanol in dichloromethane, 1 l; 2% methanol in dichloromethane, 1 l). The material thus obtained weighed 2.93 g (84%) as white crystals. Recrystallization from hot ethanol (60 ml) gave 2.2 g of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide as white crystals, m.p.=163°-164° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[O:2].I[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:11]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCOc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
4-formyl-phenol (5 g, 41 mmol), iodohexane (10.5 g, 49 mmol) and K2CO3 (8.5 g, 61 mmol) in acetonitrile (150 ml) were refluxed overnight under N2. After being cooled to room temperature, water (10 ml) was added and acetonitrile was evaporated. Water (150 ml) and Et2O (150 ml) were then added. The ethereal layer was extracted and washed with water (2×100 ml), brine (100 ml), dried over MgSO4, filtered and evaporated to dryness to afford 8.3 g (98%) of compound 1 as a slightly yellow oil after during at 80° C. under vacuum.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:15].[Na+].[OH-].[Na+].Cl[O-].[Na+]>O.CO>[CH2:1]([C:8]1[CH:13]=[C:12]([I:15])[CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1Cc1ccccc1
Reactant: [I-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1ccc(I)cc1Cc1ccccc1
Reaction time: 8 h
Yield: 87.3 %

Procedure:
6.87 g of 2-benzylphenol, 7.2 g of sodium iodide and 1.7 g of sodium hydroxide were added to 60 ml of methanol and while stirring in an ice bath, 50 ml of an aqueous 5% sodiumhypochlorite solution was added dropwise to the mixture over 30 minutes. The temperature was slowly returned to room temperature and the stirring was continued overnight. Water was added to the reaction mixture, which then was extracted with ethyl acetate, washed with brine and then dried over anhydrous magnesium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give 10.1 g of the title compound.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:16]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]>O1CCOCC1.C1(C)C=CC=CC=1>[ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(C2=CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Hydrogen chloride (20 mL of a 4N solution in dioxane) was added dropwise to a solution of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3.0 g; 9.86 mmol; 1.0 eq.) in toluene (15 mL). The reaction mixture was stirred at RT for 3 h. The formed suspension was filtered, washed with toluene (10 mL) and dried under vacuum to give the title compound as a white solid (1.96 g, 97%). UPLC/MS: (MS+) 205.3.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.CN(C=O)C.S(Cl)([Cl:22])=O>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:22])=[O:14]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCCCCCCBr
Temperature: 39 °C
Yield: 36.9 %

Procedure:
20.0 g of 11-bromoundecanoic acid (0.0754 mol) are placed in 20 ml dichloromethane in the presence of 0.28 g DMF (0.05 eq). The reaction mixture is heated to reflux and 10.68 g of thionyl chloride (0.0905 mol) are added drop wise over a period of 1 h 40 min at 39° C. After 3 h at 39° C. the reaction mixture is cooled down to r.t. and evaporated to dryness, yielding to 7.9 g of the expected compound.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC([O-])=O.[Na+].C[O:36][CH:37]1[CH:41]([CH:42]=O)[CH2:40][CH:39](OC)O1>C(Cl)Cl.O>[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([N:29]5[CH:39]=[CH:40][C:41]([CH:37]=[O:36])=[CH:42]5)[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Reactant: COC1CC(C=O)C(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](n5ccc(C=O)c5)C4)n23)cc1
Temperature: 40 °C
Yield: 33.3 %

Procedure:
To a suspension of (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.175 g, 0.373 mmol, prepared using E from Preparation #B.1 and HCl) and NaOAc (0.100 g, 1.22 mmol) in DCM (3 mL) and water (2 mL) was added 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (0.600 g, 3.37 mmol). The reaction was heated to about 40° C. for about 24 h. The reaction mixture was diluted with DCM (30 mL) and washed with water (4×20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give a brown residue. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 20-100% EtOAc in DCM to give 1-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)-1H-pyrrole-3-carbaldehyde (0.059 g, 33%) as a yellow amorphous solid: LC/MS (Table 1, Method a) Rt=2.10 min; MS m/z: 475 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([Cl:19])[CH:11]=3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>C(Cl)Cl>[Cl:19][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([C:17]#[N:18])=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH:7]=[N:6][CH:5]=3)[N:9]2[CH3:20])=[CH:14][CH:13]=1
Reactant: Cn1c(-c2cncc(N)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 211, 85 mg, 0.3 mmol) in DCM (15 mL) is added triethylamine (122 mg, 1.2 mmol) and ethanesulfonyl chloride (77 mg, 0.6 mmol) and the reaction mixture is stirred overnight. The solvent is removed and the residue is redissolved in methanol (15 mL). Aqueous 1M NaOH (1 mL) is added and the reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (methanol in dichloromethane gradient) to give ethanesulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.3 Hz, 3H), 3.23-3.33 (m, 2H), 3.79 (s, 3H), 7.36 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.90 (t, J=2.3 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 8.61 (d, J=2.3 Hz, 2H), 10.43 (s, 1H). HRMS (ESI) m/z 375.0692 [(M+H)+ Calcd for C17H16ClN4O2S: 375.0682].
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=O)[C:19](=[O:22])[C:18]=3[O:23]C)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>CO.C(Cl)(Cl)Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:18](=[O:23])[C:19](=[O:22])[C:20]=3[NH:34][CH2:33][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: NCCc1ccc(Cl)cc1
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N=C(N)Nc1nc(C2CCCC(Nc3c(NCCc4ccc(Cl)cc4)c(=O)c3=O)C2)cs1
Reaction time: 5 h

Procedure:
To a solution of 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.19 g.) in 35 ml. of methanol/chloroform (50:50 v/v) was added 2-(p-chlorophenyl)ethylamine (0.18 g.) and the resulting mixture allowed to stand at room temperature for 5 hours. After heating under reflux for 2.5 hours the reaction mixture was cooled and the precipitated buff-coloured solid collected to give 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-[2-(p-chlorophenyl)ethylamino]cyclobutene-3,4-dione. The n.m.r. spectrum in d6 dimethylsulphoxide included resonances at 1.2 (m), 1.8 (m), 2.5 (t), 3.7 (m), 6.24 (s), 6.78 (br s).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21]I>C1COCC1.O>[CH3:21][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1cccc(Nc2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1cccc(C(=O)O)c1
Reaction time: 0.17 h
Yield: 30 %

Procedure:
NaH 60% in mineral oil (0.050 g; 1.23 mmol) was added to a solution of ethyl 3-(phenylamino)benzoate (0.198 g; 0.820 mmol) in THF (3 mL). After stirring the resulting solution for 10 minutes, methyl iodide (0.102 mL; 1.1.64 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted in water and extracted with ethyl acetate. The organic layer was washed with brine and dried to yield 0.056 g (30%) of the title compound as a colourless solid which was used without further purifications.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:14])[N:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:14])[N:3]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCCc1cc(Cl)nc(SCC#N)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(NCc2ccc(Cl)cc2)nc(SCC#N)n1

Procedure:
A stirred suspension of 13.62 g. (0.06 mole) of (4-chloro-6-propyl-2-pyrimidinylthio)acetonitrile, 8.40 g. (0.06 mole) of p-chlorobenzylamine and 6.36 g. (0.06 mole) of sodium carbonate was heated under reflux in 150 ml of ethanol for five hours. The mixture was filtered and the filtrate was evaporated in a rotary evaportor. The residue was dissolved in ether (150 ml) and extracted with 150 ml of 10% concentrated hydrochloric acid solution. The ether layer was dried over magnesium sulfate, filtered and evaporated in a rotary evaporator. This residue was dissolved in benzene, diluted with a little heptane and was cooled in ice. The precipitate which formed was collected and recrystallized a second time from a benzene-heptane mixture to give 3.6 g. of product, m.p. 68°-70°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:28]([NH:27][CH2:25][CH3:26])=[O:29])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Reactant: CCN=C=O
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)NCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 55.8 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.53 mmol) in dichloromethane (10 ml) was stirred with ethyl isocyanate (0.12 ml, 1.53 mmol) at room temperature for two hours. Water was added and the organic phase separated, dried and evaporated to give crude product, which was chromatographed on silica gel, eluting with dichloromethane/methanol (95/5) to give 0.34 g of 6-nitro-2,2-dimethyl-3-(N'-ethylureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 197° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=O)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>ClCCl>[N:27]1([N:33]=[CH:25][C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NN1CCCCC1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Solvent: CCO
Product: C(=NN1CCCCC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Yield: 107 %

Procedure:
To a solution containing 342 mg (1.01 mmol) of 1-trityl-1H-imidazole-4-carbaldehyde and 100 mg (1.0 mmol) of piperidin-1-ylamine are added 3.5 mL of ethanol and 1.5 mL of dichloromethane. The reaction medium is heated at 80° C. for 1 hour. The solvents are evaporated off and 450 mg of a powder are obtained and used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=2)[N:3]=1
Reactant: COc1cccc(CN)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: COc1cccc(CNc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3-methoxybenzylamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[N-:35]=[N+]=[N-].[Na+]>CS(C)=O.O.[Cu]I.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>[NH2:35][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(N)c2s1
Temperature: 110 °C
Yield: 92.3 %

Procedure:
Ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (306 mg, 0.56 mmol), trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexane (24 mg, 0.17 mmol), sodium azide (73 mg, 1.12 mmol) and sodium ascorbate (6 mg, 0.028 mmol) were stirred in DMSO-water 1:1 (3 ml) which had been degassed with N2. CuI (1.1 mg, 0.0056 mmol) was added and the tube purged with N2, sealed and heated to 110° C. for 2 h. The mixture turned black and evolution of gas was observed. LCMS after this time indicated 34% conversion to the desired amine and starting material remaining. Additional equivalents of all reagents were added and the reaction was heated to 110° C. for a further 2 h. LCMS after this time indicated 75% conversion to the desired material. The solvents were removed under reduced pressure and the resulting residue was triturated with water. The resulting solid was isolated by filtration and dried to afford the crude product (250 mg, 73% purity by LCMS) (92%). This material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[CH3:34][NH:35][CH3:36]>>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[OH:9])[CH:17]=2)[N:22]=[C:21]([N:35]([CH3:36])[CH3:34])[C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: CNC
Product: CN(C)c1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 85 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (124 mg, 0.251 mmol, Example 65) was treated with dimethylamine (2 M in MeOH, 2 mL, 4 mmol) and the resulting suspension was heated in a sealed tube in an 85° C. oil bath for 2 days. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (Biotage NH column, 0-1% MeOH-DCM) to provide the title compound as a cream-colored foam. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.20 Hz, 1H), 7.72 (d, J=8.80 Hz, 1H), 7.43-7.52 (m, 3H), 7.34-7.43 (m, 3H), 7.22-7.34 (m, 6H), 6.33 (s, 1H), 3.36 (s, 3H), 2.72 (s, 6H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1cccnc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of t-butyl bromoacetate (2 g, 10 mmol), 3-hydroxypyridine (1.5 g, 15 mmol), and K2CO3 (2.9 g, 21 mmol) in THF (20 mL) is stirred at 60° C. After 0.5 h, the reaction mixture is cooled down at room temperature and diluted with H2O, then extracted with EtOAc. The organic phase is washed with H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give the title compound MS: 210 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 1.85 min.