Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[C:23]([Cl:39])=[CH:22][N:21]=1>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.043 g, 44%). MP: 61-70° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.33 (s, 1H), 8.52 (d, 1H, J=8.3 Hz), 8.14 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.50 (s, 1H), 7.26-7.21 (m, 1H), 6.65 (s, 1H), 5.91 (tt, 1H, J=56.1 Hz and 4.2 Hz), 3.87 (s, 3H), 2.97-2.69 (m, 16H). MS: 567.46 (MH)+.
Reaction SMILES: C=O.[C:3]([BH3-])#[N:4].[Na+].[Br:7][C:8]1[C:13](N)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][N:9]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CC(O)=O>[Br:7][C:8]1[C:13]([CH2:3][NH2:4])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][N:9]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1Br
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CC(=O)O
Product: NCc1cc(-c2ccc(Cl)cc2)cnc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.32 mL (17.63 mmol) of formalin solution (37% in water) and 443 mg (7.05 mmol) of sodium cyanoborohydride were added to a solution of 0.50 g (1.76 mmol) of 2-bromo-5-(4-chlorophenyl)pyridin-3-ylamine (Example 16.1c) in 20 mL of acetonitrile, the mixture was acidified to pH 4 with HOAc, and stirred for 16 hours at RT. The reaction mixture was acidified with 4M aqueous HCl and stirred for 1 hour at RT. It was made alkaline with sat. aqueous sodium carbonate solution and the aqueous phase was exhaustively extracted with DCM. The combined organic phases were dried over magnesium sulfate and evaporated down in vacuo. The residue was purified by chromatography (silica gel, gradient PE/DCM 50:50→100:0). Yield: 0.24 g (46% of theoretical); C12H10BrClN2 (M=297.578); calc.: molpeak (M+H)+: 297/299/301 (BrCl); found: molpeak (M+H)+:297/299/301 (BrCl); HPLC-MS: 6.09 minutes (method B).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][OH:30])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16].O[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:48][C:47]([CH3:49])=[C:46]([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:45]=2)=[CH:40][CH:39]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][O:30][C:38]3[CH:39]=[CH:40][C:41]([C:44]4[O:48][C:47]([CH3:49])=[C:46]([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:45]=4)=[CH:42][CH:43]=3)=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16]
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)oc1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(OCCc3cnc4c(c3)C(=O)N(C)c3cccnc3N4CC)cc2)oc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.6 %

Procedure:
DIAD (60 μL, 0.31 mmol) was added dropwise to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (75.8 mg, 0.25 mmol), ethyl 5-(4-hydroxyphenyl)-2-methyl-3-furanecarboxylate (75 mg, 0.30 mmol) and PPh3 (80.0 mg, 0.30 mmol) in THF (3 mL) at 25° C. The reaction mixture was stirred at 25° C. for 48 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 3:2) to give the title compound (64 mg, 48% yield) as yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[N:57]1([CH2:62][CH2:63][CH2:64][NH2:65])[CH2:61][CH2:60][CH2:59][CH2:58]1.[OH-].[Na+]>O.ClCCl.C(N(CC)CC)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:65][CH2:64][CH2:63][CH2:62][N:57]5[CH2:61][CH2:60][CH2:59][CH2:58]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCCN1CCCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C(=O)NCCCN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
To a mixture of 0.0524 g (0.117 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.049 g (0.13 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 2 mL of dichloromethane, 0.11 mL of triethylamine was added followed by 0.0174 g of 3-pyrrolidin-1-yl-propylamine. After 2 hours, 6 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-methanol-ammonium hydroxide (83:17:1.5) to give 0.0303 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3-pyrrolidin-1-yl-propyl)-benzamide (I-80).
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1)[CH3:2].N1C=CC=CC=1CO>>[CH3:2][C:1]1[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:6][O:7][C:3]=1[CH3:4]
Reactant: CCc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Agent: OCc1ccccn1
Product: Cc1onc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)c1C

Procedure:
The title-compound was prepared from 6-chloro-3-(4,5-dimethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine prepared in Example 32 part a and 2-pyridylcarbinol using the procedure given for Example 1, 1H NMR (360 MHz, CDCl3) δ 2.30 (3H, s, Me), 2.49 (3H, s, Me), 5.73 (2H, s, CH2O), 7.29 (1H, m, Ar—H), 7.70-7.83 (3H, m, 3 of Ar—H), 7.96 (1H, m, Ar—H), 8.31 (1H, d, J=8.3 Hz, Ar—H), 8.64-8.70 (2H, m, 2 of Ar—H); MS (ES30) m/e 373 [MH]+; Anal. Found C, 64.38; H, 4.05; N, 22.60. C20H16N6O2 requires C, 64.50; H, 4.33; N, 22.57%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].Cl.Cl[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:7]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[O:3][CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)#[N:8]
Reactant: N#Cc1cccc(O)c1
Reactant: ClCCc1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCCc2c[nH]cn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
240 mg (60% in oil; 6 mmol) of sodium hydride are added to a solution of 1.43 g (12 mmol) of 3-hydroxybenzonitrile in 10 ml of dimethylformamide and the mixture is stirred at room temperature for 1 hour under nitrogen. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalytic amount) are added and the mixture is heated for 3 hours at 80° C. The solvent is evaporated under reduced pressure and the oily residue is stirred in ethanol and filtered. The filtrate is evaporated and the residue is purified by chromatography on a column of silica gel (first eluent chloroform, second eluent 95/5 chloroform/methanol). The title compound is converted to the oxalate and crystallized from a 2/1 ethanol/diethyl ether mixture, M.p.: 189°-190° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)ccc1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c(CBr)c1

Procedure:
A mixture of 18.9 g (100 mmol) of 2-bromo-5-fluorotoluene, 17.8 g (100 mmol) of N-bromosuccinimide, 400 mg of benzoyl peroxide, and 200 ml of CCl4 were refluxed for 2 h. The resulting mixture was filtered through a glass frit (G2), and the precipitate was additionally washed with 3×50 ml of CCl4. The combined filtrate was evaporated to dryness. Fractional distillation of the residue (bp 92-96° C./ 4 mm Hg) gave the title product as colorless oil. Yield 19.0 g (71%).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]3[N:26]4[CH2:27][CH2:28][CH2:29][N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:25]4=[N:24][C:18]=3[CH:19]=[N+:20]2[O-])=[CH:15][CH:14]=1.[OH-].[NH4+:39]>ClCCl.O>[NH2:39][C:19]1[C:18]2[N:24]=[C:25]3[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:17]=2[C:16]2[C:21](=[CH:22][C:13]([Br:12])=[CH:14][CH:15]=2)[N:20]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCn2c1nc1c[n+]([O-])c3cc(Br)ccc3c12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCn2c1nc1c(N)nc3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Toluenesulfonyl chloride (441 mg, 2.3 mmol) was added to a mixture of tert-butyl 3-bromo-5-oxido-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate (0.97 g, 2.3 mmol), dichloromethane (30 mL), and concentrated ammonium hydroxide (3 mL), and the reaction was stirred overnight at room temperature. Water and dichloromethane were added. The aqueous layer was separated and extracted four times with dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with a gradient of 2% ammonium hydroxide/methanol in dichloromethane), and the resulting product was recrystallized from 1,2-dichloroethane and hexanes to provide 0.16 g of tert-butyl 6-amino-3-bromo-10,11-dihydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline-8(9H)-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[S:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[S:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=4)=[O:21])=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)s1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Temperature: 78 °C
Yield: 65 %

Procedure:
5-Acetyl-thiophene-2-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.959 g, 2.37 mmol) and ethyl formate (0.60 mL, 7.43 mmol) were dissolved in anhydrous ethanol (10 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.8 mL, 7.50 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.666 g, 1.54 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@H:23]5[CH2:28][CH2:27][N:26]([CH3:37])[CH2:25][C@@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@H]1CCNC[C@@H]1F
Product: CN1CC[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S,4S)-3-fluoro-1-methyl piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S,4S)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (from Example 382) and formaldehyde following General Procedure R.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])=[CH:16][CH:15]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1ccc(COc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
A mixture comprising ethyl 3-hydroxybenzoate (5.00 g), 4-methylbenzyl chloride (4.78 ml), potassium carbonate (6.24 g), methyl iodide (5.41 g) and acetone (50 ml) was heated at reflux for 15 hours. After the reaction mixture was evaporated under reduced pressure to remove the solvent, the residue was mixed with water (200 ml) and was extracted with ethyl acetate. After the organic layer was concentrated, a 1 N aqueous solution of sodium hydroxide (50 ml) was added to the residue dissolved in methanol (50 ml), and the resulting mixture was heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was evaporated under reduced pressure to remove the solvent. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 3-(4-methylbenzyloxy)benzoic acid (5.92 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:18][C:5]1[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:25][C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1NC1COC2C(O)COC12
Reactant: Cn1cc(N)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1COC2C(O)COC12
Temperature: 150 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a suspension of 6-((2-chloro-5-methylpyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-ol (54 mg, 0.20 mmol) in n-BuOH (1 mL) was added 1-methyl-1H-pyrazol-4-amine (32 mg, 0.24 mmol) and DIPEA (78 mg, 0.60 mmol). Then the mixture was stirred under nitrogen atmosphere at 150° C. overnight and concentrated in vacuo. To the residue was added water (20 mL), and extracted with DCM (20 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude oil. Then it was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to give the title compound as an off-white solid (46 mg, 70%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.[Br-].[CH3:14][CH:15]([CH3:18])[CH2:16][Zn+].CN1C=CN=C1.ClCCl>CN1CCCC1=O>[CH2:14]([C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1)[CH:15]([CH3:18])[CH3:16]
Reactant: CC(C)C[Zn+]
Reactant: N#Cc1ccc2sc(Br)nc2c1
Agent: Cn1ccnc1
Agent: [Br-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)Cc1nc2cc(C#N)ccc2s1
Yield: 41.5 %

Procedure:
Heat 2-bromo-benzothiazole-5-carbonitrile (0.3 g, 1.26 mmol) in 1-methyl-pyrrolidinone (4.2 mL) with 2-methylpropylzinc bromide (5 mL, 2.5 mmol, 0.5M solution in THF), N-methylimidazole (0.15 g, 1.88 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20.5 mg, 0.025 mmol) at 80° C. for 3 h. Cool the mixture and partition between diethyl ether and brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 1:1 gradient) to give the desired intermediate (113 mg, 42%). MS (EI) m/z: 216 (M+).
Reaction SMILES: C(OC([N:11]1[CH:17]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([Br:27])[CH:25]=[CH:26][C:20]=3[N:19]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.Br.[CH3:29][O:30][C:31]([NH:33][CH:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH3:29][O:30][C:31](=[O:32])[NH:33][CH:34]([C:35]([N:11]1[CH:17]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([Br:27])[CH:25]=[CH:26][C:20]=3[N:19]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:36])[CH:38]([CH3:40])[CH3:39]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1nc2ccc(Br)cc2[nH]1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc2ccc(Br)cc2[nH]1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (301 mg, 0.706 mmol) was dissolved in DCM (10 mL) and HBr (33 wt % in AcOH, 5 mL) was added. After 2 h the reaction mixture was concentrated and placed under hi-vac. The residue was co-evaporated with PhMe, MeOH, then again with PhMe and MeOH and placed under hi-vac. The residue was treated with 2-Methoxycarbonylamino-3-methyl-butyric acid (130 mg, 0.741 mmol, HATU (282 mg, 0.741 mmol) and DMF (7 mL). The reaction mixture was cooled to 0° C. then DIPEA (0.615 mL, 3.53 mmol) was added before warming to room temperature. After 30 minutes, the reaction mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (50% to 80% EtOAc/hexane) to afford {1-[6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (238 mg, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN1CCCC1=O.ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2c[nH]cn2)c1
Reactant: Brc1ccccn1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(-c2cn(-c3ccccn3)cn2)c1
Temperature: 160 °C
Yield: 9.2 %

Procedure:
A solution of 4-(3-cyanophenyl)imidazole (0.02 g, 0.11 mmol) in N-methylpyrrolidinone (0.5 mL) was treated with 2-bromopyridine (1.05 mL, 11.1 mmol) and the reaction mixture heated overnight at 160° C. After cooling the reaction mixture was diluted with dichloromethane (40 mL) and the organic phase was successively washed with water (10×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexanes afforded 2.5 mg (9%) of 4-(3-cyanophenyl)-1-(2-pyridyl)-1H-imidazole, as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:18])[CH2:10][CH2:11][CH:12]1OCCC[O:13]1.C(O)(=O)C(O)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:18])[CH2:10][CH2:11][CH:12]=[O:13]
Reactant: C=C(CCC1OCCCO1)c1ccc(Cl)cc1Cl
Agent: O=C(O)C(=O)O
Solvent: O
Product: C=C(CCC=O)c1ccc(Cl)cc1Cl
Yield: 85.5 %

Procedure:
A mixture of 2-[3-(2,4-dichlorophenyl)but-3-en-1-yl]-1,3-dioxane (13.5 g) and oxalic acid (8.0 g) in water (100 ml) was heated in a flask fitted with a steam inlet and an anti-splash still head and condenser. The distillate, collected until almost no immiscible oily globules remained in the reaction flask, was extracted with diethyl ether. The extracts were washed with aqueous sodium bicarbonate and aqueous sodium chloride, the dried over magnesium sulphate and concentrated under reduced pressure to give 4-(2,4-dichlorophenyl)pent-4-enal (9.21 g, 86%), containing a trace of the reactant, as a pale yellow oil, 1H nmr (CDCl3): δ9.84 (1H, t J 2 Hz, CHO).
Reaction SMILES: [O:1]1[C:5]2C=CC=C[C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[NH:35][C:36](=[O:40])[CH2:37][O:38][CH3:39])[CH2:24][CH:23]2[OH:41])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[NH:35][C:36](=[O:40])[CH2:37][O:38][CH3:39])[CH2:24][C:23]2=[O:41])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: COCC(=O)Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCC(=O)Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-methoxyacetylaminophenyl)piperidin-3-ol (1.1 g) obtained in Step 3 in 5 ml of dimethyl sulfoxide, was added dropwise 1.2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.9 g) was added to the reaction mixture, which was then stirred for about 4 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 820 mg of the titled compound.