Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH:4]=1.[CH2:19]([NH2:22])[CH2:20][OH:21].CCN(C(C)C)C(C)C>CCCCO>[N+:16]([C:12]1[CH:11]=[C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:22][CH2:19][CH2:20][OH:21])[CH:4]=2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc(Nc2cc(Cl)ncn2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=[N+]([O-])c1cccc(Nc2cc(NCCO)ncn2)c1
Temperature: 200 °C
Yield: 57 %

Procedure:
73 mg of 6-chloro-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride, 23 mg 2-ethanolamine and 81 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH=10:1. 2-(6-(3-Nitrophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].[H][H]>[Ni].C(O)C>[CH3:5][CH:4]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:2][OH:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCO
Reaction time: 144 h
Yield: 88 %

Procedure:
Under nitrogen in a 1 liter 3-neck flask equipped with mechanical stirring, Raney Nickel (Raney 2800, Aldrich, 30% slurry in water, 20.4 g) was suspended in ethanol (400 mL). A solution of farnesol (mixture of cis and trans isomers, 25.0 g), in ethanol (75 mL) was added dropwise with a gentle sweep of hydrogen through the reaction mixture, and the mixture was stirred under hydrogen for 144 hours. Hydrogen was then replaced by nitrogen, and under a positive pressure of nitrogen the suspension was filtered through a filter stick. The catalyst was suspended in a small volume of ethanol and the filtration was repeated. Finally the catalyst was suspended in water and the suspension was rejected. The ethanol filtrate was filtered again through celite and the filtrate was concentrated. After extractive work-up using toluene, the residue was distilled under vacuum. The desired product, by 112-115° C., was obtained as a colorless liquid, 22.76 g (88% yield). Mass spec: m/z 226 (M−2)+. Anal. Calcd for C15H32O: C, 78.88%; H, 14.12%. Found: C, 77.90%; H, 14.32%. No hydrocarbon was detected in the fore-run (0.28 g) or distillation residue (0.9 g). The alcohol product was converted to the corresponding bromide, without additional purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:24])[CH:21](O)O)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([NH2:36])[CH3:35])=[CH:29][CH:28]=1>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:24])[CH:21]=[N:36][CH:34]([CH3:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)N)cc1
Reactant: O=C(c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12)C(O)O
Solvent: CS(C)=O
Product: COc1ccc(CC(C)N=CC(=O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
10.84 g of 8-benzyloxy-5-(dihydroxyacetyl)carbostyril 1/3 hydrate and 5.66 g of N-(2-(p-methoxyphenyl)-1-methylethyl)amine are dissolved in 100 ml of dimethylsulfoxide, and the solution is stirred at room temperature for one hour. The mixture is extracted with chloroform, and the extract is washed with water and a saturated sodium chloride solution, successively. The chloroform solution is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with a mixture of ethyl acetate and n-hexane, and crystalline precipitates are collected by filtration. 13 g of 8-benzyloxy-5-{1-oxo-2-[N-(2-(p-methoxyphenyl)-1-methylethyl)imino]ethyl}carbostyril are obtained as yellow solid. Yield: 87.6%
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[CH3:12][NH:13][OH:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:39])[C:23]2[CH:28]=[N:27][C:26]([C:29]([O:31]C)=O)=[C:25]3[O:33][C:34]([CH3:38])([CH3:37])[O:35][CH2:36][C:24]=23)=[CH:18][CH:17]=1.O>O1CCCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([OH:39])[C:23]2[CH:28]=[N:27][C:26]([C:29]([N:13]([OH:14])[CH3:12])=[O:31])=[C:25]3[O:33][C:34]([CH3:38])([CH3:37])[O:35][CH2:36][C:24]=23)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Reactant: CNO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(O)C(=O)c1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Temperature: 78 °C
Reaction time: 0.17 h
Yield: 13.7 %

Procedure:
1.8 mL of lithium bis(trimethylsilyl)amide solution (1.809 mmol, 9 eq, 1M in tetrahydrofuran) was added to 0.041 g of N-methylhydroxylamine hydrochloride (0.249 mmol, 1.1 eq.) in 5.0 mL of tetrahydrofuran (−78° C.) and stirred for 10 min at 78° C. 0.070 g of methyl 5-((4-fluorophenyl)(hydroxy)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate solution (0.201 mmol, 1 eq.) in 3.0 mL of tetrahydrofuran was then added followed by stirring for 30 min at −78° C. Water was then added to the reaction mixture followed by extraction with ethyl acetate. The resulting organic phases were then combined and concentrated under reduced pressure yielding 0.01 g of crude product (14% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(=O)(O)[O-].[Na+]>O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 165 °C
Yield: 91.6 %

Procedure:
A heterogeneous mixture of 2-amino-4-fluorobenzoic acid (8.7 g, 56 mmol) and formamidine acetate (29.2 g, 280 mmol) was stirred and heated at 165° C. for 2 h. The reaction mixture was suspended in H2O and the mixture was carefully basified with saturated sodium bicarbonate solution followed by stirring for 1 h. The brown solid was collected by filtration, washed with H2O and air dried to afford 8.42 g (91%) of 7-fluoroquinazolin-4(3H)-one. MS 165.0 (ES+).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[F:9][C:10]([F:24])([C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:12][OH:13]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:7][CH2:12][CH2:11][C:10]([F:9])([F:24])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])(=[O:8])[C:2]([CH2:4][C:5]([O:13][CH2:12][CH2:11][C:10]([F:24])([F:9])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])=[O:6])=[CH2:3]
Reactant: C=C1CC(=O)OC1=O
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(CC(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 68.7 %

Procedure:
13.5 g (0.12 moles) of itaconic anhydride, 69.8 g (0.26 moles) of 3,3,4,4,5,5,6,6,6-nonafluorohexanol, and 1.14 g (6 millimoles) of p-toluene sulfonic acid first hydrate were heated and refluxed in 500 mL of toluene for 12 hours, while distilling off water which was generated therein. Then, the mixture was cooled to room temperature, to this ethyl acetate was added, and an organic phase was washed with 1 mol/L of sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution to obtain 51.3 g (69% yield) of compound as oil-state compound.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21](O)=[O:22])[CH:16]=3)[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[NH:3]1.[NH:28]1[C:38]2[C:39]3[CH:30]([CH2:31][C:32](=[O:40])[NH:33][C:34]=3[CH:35]=[CH:36][CH:37]=2)[CH2:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:1]=[C:2]1[NH:3][C:4]2[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=2[CH2:6][CH2:7][N:8]1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([C:21]([N:28]3[C:38]4[C:39]5[CH:30]([CH2:31][C:32](=[O:40])[NH:33][C:34]=5[CH:35]=[CH:36][CH:37]=4)[CH2:29]3)=[O:22])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: O=C(O)c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ncn1
Reactant: O=C1CC2CNc3cccc(c32)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C1CC2CN(C(=O)c3cc(N4CCC(N5CCc6ccccc6NC5=O)CC4)ncn3)c3cccc(c32)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63mg (0.17 mmol) 6-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 30 mg (0.17 mmol) 1,2,2a,5-tetrahydro-3H-pyrrolo-[4,3,2-de]quinolin-4-one in 56 μL (0.40 mmol) TEA and 1.8 mL DMF were mixed with 58 mg (0.18 mmol) TBTU and the mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: Cl.Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][CH2:58]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117, see example 72) and amine 21 analogously to the method described in example 1.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=[N:13][CH:14]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cncc(CO)c2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cncc(COS(C)(=O)=O)c2)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-3-yl]-methanol (195 mg, 1.00 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.18 mL, 1.29 mmol) followed by DMAP (12 mg, 0.10 mmol) and Ms-Cl (0.10 mL, 1.26 mmol). After stirring at 0° C. for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.66 min; [M+H]+=274.27.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][O:4][CH:3]1[N:7]1[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH:9]=[N:8]1.CC(C)([O-])C.[K+].CS(C)=O>C(O)(=O)C>[O:4]1[CH2:5][CH:6]=[CH:2][CH:3]1[N:7]1[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH:9]=[N:8]1
Reactant: O=c1cnn(C2OCCC2Cl)c(=O)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=c1cnn(C2C=CCO2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Chloro-tetrahydro-2-furanyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (0.8 g) and potassium t-butoxide (0.7 g) are added to dimethyl sulfoxide (3 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water. The mixture is acidified with acetic acid and extracted with chloroform. The chloroform extract is washed with water, dried and evaporated to remove the solvent. The crude residue is recrystallized from ethanol to give 2-(2,5-dihydro-2-furanyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 81). Yield, 0.5 g (76%). M.P., 147°-148° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]3[C@H:33]([C:34]([F:37])([F:36])[F:35])[CH2:32][C:31](=[O:38])[NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)(=O)=O.CN(C)C=O.[NH:44]1[CH2:47][CH2:46][CH2:45]1>C(OCC)(=O)C>[N:44]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]2[CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]4[C@H:33]([C:34]([F:36])([F:35])[F:37])[CH2:32][C:31](=[O:38])[NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:22][CH2:23]2)[CH2:47][CH2:46][CH2:45]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)OCCn1cc(CC(F)(F)F)nc1C1CCN(c2ncnc3c2[C@H](C(F)(F)F)CC(=O)N3)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C[C@@H](C(F)(F)F)c2c(ncnc2N2CCC(c3nc(CC(F)(F)F)cn3CCN3CCC3)CC2)N1
Temperature: 50 °C

Procedure:
Combine (R)-2-(2-(1-(7-oxo-5-trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethyl methanesulfonate (1.04 g, 1.82 mmol), dimethylformamide (9.3 mL), and azetidine (1.11 mL, 9.0 eq) under nitrogen. Heat the reaction mixture at 50° C. overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash the organic layer with water. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with 10% methanol/dichloromethane to 10% 2 M ammonia in methanol/dichloromethane, to give the title compound, (R)-4-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one, as a white solid (0.49 g, 51%). MS (ES) m/z=532 [M]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.BrCCBr.[Mg].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:14][Si:15]([CH3:18])([CH3:17])[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1cccc([Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of m-chlorotoluene (12.66 g, 0.100 mol) and 1,2-dibromoethane (0.5 ml) in THF (20 ml) was added to magnesium turnings (2.67 g, 0.110 mol). The mixture was heated under reflux for 4 h, after which the heating bath was removed and trimethylchlorosilane (11.08 g, 0.102 mol) was added so that gentle reflux was maintained. The mixture was stirred for another 0.5 h and 5% NaHCO3 (100 ml) was then added. The resulting mixture was extracted with CH2Cl2 (3×50 ml), the organic phase was washed with brine and dried (MgSO4). Filtration and evaporation provided 15.05g (92%) of 36 as a pale yellow liquid. Spectroscopic data were identical to those previously reported in the literature.40
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Reaction time: 8 h
Yield: 23.3 %

Procedure:
To a mixture of 0.40 g (1.55 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.188 g (1.86 mmol) of triethylamine and 15 ml of tetrahydrofuran at 0° C. is added 0.275 g (1.55 mmol) of 4-cyanobenzoyl chloride dropwise and the reaction mixture is allowed to stir overnight while slowly reaching room temperature. A precipitate is formed overnight which is collected by filtration, washed with water and ether and dried to yield a crude product which is triturated with methanol/chloroform to yield 0.14 g (23%) of the title compound as a white solid: m.p.>300° C.; m/e 386.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:53])[C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]5[N:33]=[CH:34][C:35]6[N:41]([CH3:42])[C:40](=[O:43])[C:39]([F:45])([F:44])[CH2:38][N:37]([CH:46]7[CH2:49][CH2:48][CH2:47]7)[C:36]=6[N:50]=5)=[C:27]([O:51][CH3:52])[CH:26]=4)[CH2:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[NH2:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]3[N:33]=[CH:34][C:35]4[N:41]([CH3:42])[C:40](=[O:43])[C:39]([F:45])([F:44])[CH2:38][N:37]([CH:46]5[CH2:49][CH2:48][CH2:47]5)[C:36]=4[N:50]=3)=[C:27]([O:51][CH3:52])[CH:26]=2)=[O:53])[CH2:22][CH2:23]1
Reactant: COc1cc(C(=O)N2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cc(C(=O)N2CCC(N)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A mixture of 0.150 g (0.20 mmole) of {1-[4-(9-Cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoyl]-piperidin-4-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester, 1 mL of piperidine and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.025 g of 2-[4-(4-amino-piperidine-1-carbonyl)-2-methoxy-phenylamino]-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (I-6).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32]N)[CH:27]=2)=[CH:22][CH:21]=1)[CH2:17][CH2:18][CH3:19]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:29]([C:11]4[CH2:10][CH2:9][C:8]5[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=5[C:2]=4[NH:32]3)=[CH:30][CH:31]=2)=[CH:22][CH:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1ccc(-c2cccc(NN)c2)cc1
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(C(=O)O)cc2CC4)cc1
Temperature: 105 °C

Procedure:
A sample of commercially available 5-Oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (75 mg, 0.39 mmol) and (4′-Butyl-biphenyl-3-yl)-hydrazine hydrochloride (115 mg, 0.41 mmol) are treated with zinc chloride (134 mg, 0.99 mmol) and acetic acid (5 mL). The reaction is then heated to 105° C. overnight and cooled to room temperature. The reaction is filtered and the filtrate is washed with methanol and dried on the high vacuum line to afford the title material as a single regioisomer. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.90-7.84 (m, 2H), 7.75-7.71 (m, 1H), 7.62-7.57 (m, 4H), 7.35-7.31 (m, 1H), 7.28 (d, J=8.0 Hz, 2H), 3.11-3.05 (m, 2H), 2.99-2.92 (m, 2H), 2.62 (dd, J=7.6, 7.6 Hz, 2H), 1.65-1.55 (m, 2H), 1.40-1.29 (m, 2H), 0.92 (dd, J=7.3, 7.3 Hz, 3H); ESIMS m/z for (M++H+) calculated 396.2, found 396.2.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34](I)=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34]([C:3]3[S:4][C:5]4=[CH:6][N:7]=[CH:8][CH:9]=[C:10]4[C:2]=3[CH3:1])=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1csc2cnccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cnccc4c3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
149 mg of 3-Methyl-thieno[2,3-c]pyridine (1.0 mmol) is dissolved in 3.0 ml of dry THF and cooled to −78° C. 0.48 ml of n-BuLi 2.5M in hexane (1.2 mmol) is added at −78° C. and stirred at −78° C. for 10 min and room temperature for 10 min. The reaction vessel is cooled to −78° C. again and 2.6 ml of 0.5M ZnCl2 in THF (1.3 mmol) is added at −78° C. and stirred at room temperature for 15 min. 274 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2151431) (0.8 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) are added and the tube is capped. The tube is heated at 80° C. for 3 days. The reaction is quenched by NH4Claq. and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:1) to give 131 mg of the title compound. Yield 45%. mass spectrum (m/e): 365 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:40])[C@@H:12]([NH:21][C:22](=[O:39])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:40])[C@@H:12]([NH:21][C:22](=[O:39])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:48](=[O:50])[CH3:49])=[CH:34][CH:33]=2)[NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(N)cc2)[C@@H](C)c2ccccc2)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 2-{(2S,3S)-2-[(R)-2-(4-amino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (100 mg, 0.177 mmol) in dichloromethane (10 mL) was added triethylamine (50 μL, 0.354 mmol) followed by acetic anhydride (22 μL 0.212 mmol). The reaction mixture was then stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography over silica gel gradient eluted from 10% to 75% ethyl acetate in hexanes to afforded 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyryl-amino}-thiazole-4-carboxylic acid methyl ester which was used immediately in the following step of the synthesis (107 mg, 98%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH:9]1[CH2:10][CH2:11][O:6][CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanesulphonyl chloride (1.82 ml, 23.5 mmol) was added dropwise over 10 minutes to an ice-cold solution of tetrahydro-2H-pyran-4-ol (2.0 g, 19.6 mmol) and triethylamine (3.56 ml, 25.5 mmol) in dichloromethane (20 ml), and the reaction then stirred at room temperature for 72 hours. The reaction was washed with saturated aqueous sodium bicarbonate solution (10 ml), dried (MgSO4) and evaporated under reduced pressure to give an orange oil, that solidified on standing, 3.1 g.