Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([C@H:18]([C@@H:28]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:29]([NH:31][N:32]1[C:36](=[O:37])[C:35]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[NH:34][C:33]1=[O:43])=[O:30])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:1]1([S:7]([N:40]2[CH2:41][CH2:42][C:35]3([NH:34][C:33](=[O:43])[N:32]([NH:31][C:29](=[O:30])[C@@H:28]([C@@H:18]([C:16]([O:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:17])[CH2:19][CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:44][CH:45]([CH3:46])[CH3:47])[C:36]3=[O:37])[CH2:38][CH2:39]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCNCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCN(S(=O)(=O)c3ccccc3)CC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
In a manner analogous to that described in Example 26, part (i) but using benzenesulphonyl chloride in place of methanesulphonyl chloride from 0.83 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide there was obtained 0.889 g of N-[8-(benzenesulphonyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1.C(Cl)Cl.C(Cl)Cl>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.733 ml, 5.84 mmol) is suspended in pyridine/DCM (3 ml, 2:1). The solution is stirred at 0° C., and 3-aminopyridine (500 mg, 5.31 mmol) dissolved in DCM (1 ml) is added drop-wise. The reaction mixture is at 0° C. for 1 hour. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate. This organic portion is washed with 0.1M HCl and then concentrated in vacuo to afford the titled compound. (MH+ 215).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:13]([C:14]#[N:15])=[C:12]([F:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:3][CH3:4].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[F:16][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([C@@H:2]([NH:1][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH2:3][CH3:4])[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[C:13]=1[C:14]#[N:15]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
A mixture of 2-((S)-1-amino-propyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile (0.260 g, 0.88 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.290 g, 1.24 mmol) and DIPEA (0.28 mL, 1.59 m mol) in IPA (2 mL) was stirred at 90° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and the residue purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol and treated with HCl/dioxane (4M, 1.1 mL, 0.00450 mol) and stirred for 20 minutes. The mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) to give 244 as a white solid (0.205 g, 57%). LCMS (method K): Rt 3.51 min, [M+H]+ 413. 1H NMR (DMSO-d6): δ 13.20-12.50 (1H, bs), 9.60 (1H, s), 8.00 (1H, s), 7.71 (1H, m), 7.60 (2H, s), 7.51-7.49 (3H, m), 7.11-7.08 (1H, m), 6.86 (1H, m), 5.64 (1H, m), 2.10 (3H, s), 1.50 (3H, d, J=6.81 Hz)
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1>[CH2:3]([C@@H:2]([C:1]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7])[CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[C@H](CC(=O)OC)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-hexanoyl-4-(S)-benzyloxazolidin-2-one A-2 (7.3 mmol) in THF at −78° C. is added 1.0 M NaHMDS (8.8 mmol) and the reaction stirred at −78° C. for 1 hour. A solution of methyl bromoacetate (8.8 mmol) in THF is then added dropwise, and the resulting mixture is stirred at −78° C. for 1 hour and then at rt overnight. The reaction is quenched with NH4Cl, concentrated, then suspended in EtOAc and washed with 0.5 N HCl and brine, dried and purified by silica gel chromatography (EtOAc/hexanes) to afford the methyl 3-(R)-(n-butyl)-3-[4-(S)-benzyloxazolidin-2-one-3-ylcarbonyl)propionate (A-3).
Reaction SMILES: [NH2:1][C:2]1[CH:29]([CH3:30])[CH:6]2[CH2:7][C:8]([CH2:11][C:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:28]=[CH:27][N:26]=[CH:25]5)=[CH:20][CH:19]=4)[CH2:16][CH:17]=3)([CH3:10])[O:9][C:5]2=[C:4]([CH3:31])[C:3]=1[CH3:32].C(O)C.C(O)(=O)C.[OH-].[Na+]>[C].[Pd].O>[NH2:1][C:2]1[CH:29]([CH3:30])[CH:6]2[CH2:7][C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH:28]=[CH:27][N:26]=[CH:25]5)=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)([CH3:10])[O:9][C:5]2=[C:4]([CH3:31])[C:3]=1[CH3:32]
Reactant: CC1=C(N)C(C)C2CC(C)(CC3=CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=C(N)C(C)C2CC(C)(CC3CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Temperature: 50 °C
Reaction time: 7 h
Yield: 86.3 %

Procedure:
In an autoclave, to 0.45 g of 4-(±)-(5-amino-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine and 0.1 g of 10% palladium carbon, 5 ml of ethanol and 5 ml of acetic acid were added, followed by stirring at 50° C. under a hydrogen pressure of 10 kg/cm2 for 7 hours. The reaction solution was poured into water, neutralized with 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the resulting crystal was washed with hexane and then dried to obtain 0.39 g of the objective product (mp: 170-172° C.).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](Cl)=[O:12])(=[O:3])[CH3:2].[F:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([F:24])[C:16]=1[CH:17]=[O:18].C(N(CC)CC)C.C(Cl)Cl>O>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:23][C:21]1[CH:22]=[C:15]([F:14])[C:16]([CH:17]=[O:18])=[C:19]([F:24])[CH:20]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: O=Cc1c(F)cc(O)cc1F
Reactant: CC(=O)OC[C@@H]1CCCN1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OC[C@@H]1CCCN1C(=O)Oc1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.1 %

Procedure:
To a 250 mL dry round bottom flask were added (S)-(1-(chlorocarbonyl)pyrrolidin-2-yl)methyl acetate (6.79 g, 33.0 mmol), 2,6-difluoro-4-hydroxybenzaldehyde (4.74 g, 30 mmol), triethylamine (5.40 mL, 39.0 mmol) and anhydrous CH2Cl2 (40 mL). The resulting mixture was stirred at room temperature for 2 days, then water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (80 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give (S)-3,5-difluoro-4-formylphenyl 2-(acetoxymethyl)pyrrolidine-1-carboxylate (4.92 g) as a colorless oil. Yield: 46%. 1H NMR (CDCl3, 300 MHz, mixture of two isomers): 8=10.28 (s, 1H), 6.97 (t, J=11.4 Hz, 2H), 4.33-4.12 (m, 3H), 3.65-3.55 (m, 2H), 2.10-2.01 (m, 7H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=183.5, 170.7 (d, J=7.3 Hz), 163.6 (dd, J=262.5, 8.6 Hz), 157.0, 150.8 (d, J=14.6 Hz), 112.6, 106.2 (d, J=25.0 Hz), 64.4, 63.8, 56.8, 56.4, 47.4, 47.3, 28.7, 27.8, 23.8, 22.9, 20.8.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[N:24]1C(=O)C2=CC=CC=C2C1=O)(=[O:5])[CH2:2][CH2:3][CH3:4].O.NN>C(O)C>[NH2:24][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:15]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: CCCC(=O)c1cnc2c(N3C(=O)c4ccccc4C3=O)cccc2c1Nc1ccccc1C
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCC(=O)c1cnc2c(N)cccc2c1Nc1ccccc1C
Yield: 86.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-phthalimidoquinoline (9.0 g, 0.02 moles) and hydrazine hydrate (1.5 ml) were heated together under reflux in ethanol (100 ml) for 2 hours. The solvent was evaporated and the residue was stirred in chloroform, filtered and the filtrate concentrated and chromatographed (silica gel chloroform) to give 8-amino-3-butyryl-4-(2-methylphenylamino)quinoline (5.5 g, 86%), as a bright yellow oil which crystallized on standing, m.p. 108°-10° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]1[C:40]2[C:35](=[CH:36][C:37](O)=[CH:38][CH:39]=2)[CH2:34][CH2:33]1.CNC1C=CC=C(NC)N=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([O:13][C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[CH2:32][CH2:33][CH2:34]3)=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: CNc1cccc(NC)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)Oc2ccc3c(c2)CCC3)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 25 °C

Procedure:
To a mixture containing 2-butyl-4-chloro-1-[[1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5-carboxylic acid (903 mg, 2.03 mmol, prepared as described in part C of Example 9), 5-indanol (307 mg, 2.29mmol), 2,6-dimethylaminopyridine (50.8 mg, 0.416 mmol) and triethylamine (0.377 mL, 2.70 mmol) in 9 mL of dichloromethane cooled in an ice bath was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (519 mg, 2.70 mmol). The stoppered reaction mixture was allowed to warm to ambient temperature overnight, then diluted with methylene chloride and rinsed with water and saturated aqueous sodium chloride solution. The organic extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1.83 g of crude product. Flash chromatography on 75 g of silica gel eluted with 8:2, hexanes:ethyl acetate gave 1.03 g of the title A compound.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.[C:24]([O:32]OC(=O)C1C=CC=CC=1)(=[O:31])C1C=CC=CC=1.[Br-].[C-]#N.[K+].C(CC1C2C(=NC3C(N=2)=CC=CC=3)C=CC=1)#N>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[C:24]([CH2:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1)([OH:32])=[O:31]
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: Cc1cccc2nc3ccccc3nc12
Agent: N#CCc1cccc2nc3ccccc3nc12
Agent: O=C1CCC(=O)N1Br
Agent: [Br-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)Cc1cccc2nc3ccccc3nc12

Procedure:
Scheme 9 provides a synthetic route to the 1-carboxymethyl-5-N-ethyl phenazine derivative (42). The bromo derivative (37) is formed by reacting 1-methyl phenazine (36) (available from Apin Chemicals, UK) with N-bromosuccinimide in the presence of benzoyl peroxide and a solvent. Carbon tetrachloride is a particularly suitable solvent for the bromination reaction. Reaction of the bromide (37) with KCN in a suitable solvent, such as, for example, DMF, gives the 1-cyanomethyl phenazine derivative (38). Acid hydrolysis of the cyanophenazine (38) provides the 1-carboxymethyl phenazine (39). The acid group of compound (39) is converted to a methyl ester by reaction with methanol and HCl to give the phenazine ester (40). Ester (40) can be N-alkylated with dimethyl sulfate in the presence of potassium carbonate to give the 5-ethyl phenazine ester (41). Hydrolysis of the ester (41) with dilute hydrochloric acid provides the 5-ethyl-1-carboxymethyl phenazine (42).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[C:8]([C:10]2[C:18]3[N:17]4[CH:19]=[N:20][N:21]=[C:16]4[CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.[OH-].[Na+].C1C(=O)N(Br)C(=O)C1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+].COC1C=C([Sn](CCCC)(CCCC)CCCC)C=CN=1>CCO.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>[CH:19]1[N:17]2[C:18]3[C:10]([C:8]4[CH:7]=[CH:6][NH:5][C:4](=[O:3])[CH:9]=4)=[CH:11][NH:12][C:13]=3[N:14]=[CH:15][C:16]2=[N:21][N:20]=1
Reactant: COc1cc(-c2c[nH]c3ncc4nncn4c23)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccnc(OC)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCO
Product: O=c1cc(-c2c[nH]c3ncc4nncn4c23)cc[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
Hydrochloric acid (4 M in 1,4-dioxane, 0.300 mL, 1.20 mmol) was added to a slurry of 8-(2-methoxypyridin-4-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.016 g, 0.060 mmol, (prepared using D from Preparation #BBBBB.1 and NaOH, GGG.1 with NBS, K.1 with TsCl and NaH, CCCCC with 2-methoxy-4-(tributylstannyl)pyridine [Synthonix], tetrakis(triphenylphosphinepalladium(0), LiCl, CsF, and CuI, D with NaOH) in EtOH (0.500 mL) and water (0.050 mL). The reaction vessel was sealed and the mixture was warmed to about 80° C. After about 15 h, the mixture was warmed to about 90° C. After about 65 h, the solution was allowed to cool to ambient temperature. The volatiles were removed under reduced pressure to afford 4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyridin-2(1H)-one (0.0153 g, 94%): LC/MS (Table 1, Method a) Rt=0.73 min; MS m/z 253 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2([CH3:20])[CH2:15][CH2:16][N:17]([C:22]3[C:23]4[C:30]([CH3:31])=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:19]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C(=O)Nc2cccc(C(C)(C)C)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(C(C)(C)C)c4)CC3)c12
Temperature: 100 °C
Yield: 50 %

Procedure:
N-(3-tert-Butylphenyl)-4-methylpiperidine-4-carboxamide from step B (0.33 g, 1.07 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.18 g, 1.07 mmol), N,N-diisopropylethylamine (0.69 g. 5.34 mmol), and isopropanol (7 mL) were combined in a pressure rated sealed tube and heated at 100° C. for 18 hours. The mixture was concentrated and taken up in dichloromethane from which a precipitate (0.18 g) was collected. The solution was chromatographed (SiO2, 0-2% MeOH:CH2Cl2), and the columned material (0.15 g) was combined with the precipitate and dissolved in methanol (15 mL) at 60° C. Water was added (5.0 mL), and the mixture was cooled. The resultant precipitate was filtered, washed with water, and dried to give the title compound in 50% yield.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:38]1[C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]2[C:34]1=[O:44]
Reactant: OCCCCCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Yield: 93 %

Procedure:
Following general procedure A, 70.0 mmol (18.6 g) of 12-Bromododecan-1-ol, 77.0 mmol (20.2 g) of triphenylphosphine, 77.0 mmol (11.3 g) of phthalimide and 77.0 mmol (16.1 mL) of diisopropyl azo dicarboxylate were reacted in 350 mL of tetrahydrofuran for 2.5 h and the mixture was processed accordingly. The crude product was purified by column chromatography (cyclohexane/ethyl acetate 9:1). Yield 93%.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([NH:15][S:16]([C:19]2[CH:38]=[CH:37][C:22]([NH:23][C:24]3[N:29]=[C:28]([C:30]4[N:34]([CH3:35])[C:33]([CH3:36])=[N:32][CH:31]=4)[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])([CH3:14])[CH3:13])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][C:12]1([CH3:13])[CH2:14][N:15]1[S:16]([C:19]1[CH:38]=[CH:37][C:22]([NH:23][C:24]2[N:29]=[C:28]([C:30]3[N:34]([CH3:35])[C:33]([CH3:36])=[N:32][CH:31]=3)[CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)NS(=O)(=O)c2ccc(Nc3nccc(-c4cnc(C)n4C)n3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)N4CC4(C)C)cc3)n2)n1C
Yield: 91 %

Procedure:
To a solution of 2-{4-[N-(1-(4-toluenesulphonyloxy)-2-methylprop-2-yl)sulphamoyl]anilino}-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 81; 2.14 g, 3.75 mmol) in acetone (73 ml) was added powdered anhydrous potassium carbonate (0.57 g, 4.13 mmol). The mixture was heated at reflux for 4 hours. The reaction mixture was allowed to cool filtered and the solid washed with acetone. The filtrate was evaporated to give the title compound (1.36 g, 91%) as a white solid. NMR 1.42 (s, 6H), 2.37 (s, 3H), 2.43 (s, 2H), 3.95 (s, 3H), 7.20 (d, 1H), 7.63 (s, 1H), 7.77 (d, 2H), 7.95 (d, 2H), 8.43 (d, 1H), 10.0 (s, 1H), m/z 399.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([NH:11]C(=O)OC(C)(C)C)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3]>FC(F)(F)C(O)=O>[NH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:10]=1
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)ccn1
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1cc(N)ccn1

Procedure:
A solution of 4.4 grams (0.017 mole) of (1,1-dimethylethyl) N-(2-propoxy-4-pyridinyl)carbamate in 20 ml of trifluoroacetic acid was stirred at ambient temperature for one hour. The excess trifluoroacetic acid was removed under reduced pressure. The yield of 4-amino-2-propoxypyridine was 2.6 grams as an oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1.[BH4-].[Na+]>O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CNCc2ccc(OC)cc2)cc1
Temperature: 5 °C

Procedure:
p-Anisaldehyde (411 mmol), 4-methoxybenzylamine (411 mmol) and toluene (500 mL) were combined in a round bottomed flask fitted with a condenser and a Dean-Stark trap. The reaction was refluxed for 1 h during which water was removed from the reaction mixture. The reaction was cooled and concentrated. The residue was dissolved in MeOH (120 mL). The mixture was cooled to 5° C. and NaBH4 (205 mmol) was added in portions over 45 min. The reaction was slowly heated to reflux. After 2 h at reflux, the reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc. The organic layer was washed (3×H2O and brine), dried (Na2SO4) and concentrated to yield the desired product.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:31]N1C(=O)CCC1=O.CN(C)C=O>>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([Cl:31])[C:19](=[O:23])[N:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(=O)n(-c2ccccc2)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A mixture of 2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (13.9 mg, 0.0343 mmol) and N-chlorosuccinimide (5.33 mg, 0.0399 mmol) in N,N-dimethylformamide (0.3 mL, 4 mmol) was stirred at r.t. for 30 min. It was quenched and stirred with water (4 ml) for 5 min, then filtered, washed with water and dried in vacuo to give 10.1 mg of the title compound as a colourless solid, yield 67%. LC-MS (m/z) 439.4 & 441.6 (3:1, MH+); tR=1.52 (method C). 1H NMR (T=+70° C., 500 MHz, DMSO-d6, DMSO-d5=2.50 ppm): 1.77 (overlapping s, 3H, Me), 1.70-1.92 (overlapping m, 5H), 2.07 (br. m, 1H), 2.17 (s, 3H, Me), 2.67 (m, 1H, CH of Cb), 4.94 (t, J=8.3 Hz, CH—N), 7.03 (br. t, 1H), 7.14 (br. d, J=9.8 Hz, 1H), 7.18 (br. d, J=7.7 Hz, 1H), 7.22 (br., 2H, Ph), 7.35 (br. m, 1H), 7.5 (br. t, 1H, para-H of Ph), 7.55 (br. m, 2H, two meta-H of Ph), 8.68 (br. d, 1H, NH).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH2:16][C:15]3[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=3[N:13]=2)[CH2:8][CH2:7]1)(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH3:1][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH2:16][C:15]3[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=3[N:13]=2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCN(C2=Nc3ccccc3Cc3nccn32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C2=Nc3ccccc3Cc3nccn32)CC1
Temperature: 25 °C

Procedure:
To a solution of 0.2 g of 5-(4-carboethoxy-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine in 2 ml of dry tetrahydrofuran, 100 mg of lithium aluminum hydride are added at once and the mixture is refluxed under nitrogen for 48 hours. The mixture is cooled to room temperature, stirred with 0.2 ml of 30% sodium hydroxide, and filtered. the filtrates are evaporated to dryness and the product is purified to give 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine.