Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[C:4]2[O:13][C@:12]([C:15]([OH:17])=O)([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO[C:33](=O)[C@H:34](CC(C)C)N>>[O:29]1[CH2:34][CH2:33][O:30][CH:28]1[C@@H:20]([NH:19][C:15]([C@@:12]1([CH3:14])[CH2:11][CH2:10][C:5]2[C:4](=[C:3]([CH3:18])[C:2]([CH3:1])=[C:7]([OH:8])[C:6]=2[CH3:9])[O:13]1)=[O:17])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)O)O2
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)N[C@@H](Cc1ccccc1)C1OCCO1)O2

Procedure:
The experimental protocol used is the same as that described for Example 14, with (R)-Trolox being used instead of intermediate 12.1 and the methyl ester of L-phenylalanine replacing the L-Leucine methyl ester. Yellow oil. LC-MS: MH+=426.2.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:51]=[CH:50][CH:49]=[CH:48][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:13]1)(O)=[O:2].C[N:53](C)[CH:54]=[O:55].C(Cl)(=O)C(Cl)=O>ClCCl>[OH:55][CH2:54][NH:53][C:1]([CH2:4][CH2:5][C:6]1[CH:51]=[CH:50][CH:49]=[CH:48][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[CH2:13]1)=[O:2]
Reactant: CN(C)C=O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCCOc2ccccc2CCC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCCOc2ccccc2CCC(=O)NCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.136 g of benzyl 3-{2-[2-(2-carboxyethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 3 ml of dichloromethane is admixed with 0.01 ml of N,N-dimethylformamide and 0.034 ml of oxalyl chloride and stirred at room temperature over 2 hours. The reaction mixture is concentrated by evaporation, and the residue is dissolved in 3 ml of tetrahydrofuran, cooled to 0° C. and added dropwise to the suspension of 0.033 g of N-methylhydroxylamine hydrochloride and 0.11 ml of triethylamine in a 4:1 tetrahydrofuran/water mixture (2 ml). The reaction mixture is stirred at room temperature over 14 hours, diluted with ethyl acetate, washed successively with 1N HCl, 1M aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.40 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.53.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[Br:27][C:28]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:30](=[O:31])[C:29]4[CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=[CH:36][C:28]=4[Br:27])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Br
Reactant: CN(C)CCNc1ccnc2cc3c(cc12)OCO3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)c1cc([N+](=O)[O-])ccc1Br)c1ccnc2cc3c(cc12)OCO3

Procedure:
To a solution of compound 7 (259 mg, 1.0 mmol) and triethylamine (0.5 mL) in dry CH2Cl2 (20 mL) was added a solution of 2-bromo-5-nitrobenzoic acid chloride in 20 mL of CH2Cl2 (which was prepared by refluxing of 295 mg, 1.2 mmol of 2-bromo-5-nitrobenzoic acid in 10 mL of thionyl chloride for 3 h.) and reaction mixture was heated to reflux for 4 h. The reaction mixture was washed with saturated NaHCO3 solution, water and brine and dried over Na2SO4. The solvent was removed in vacuo to give a yellow solid; yield 350 mg (71.8%); mp 204–5° C.; 1H NMR (CDCl3) δ (2.3, s, 6H), 2.53–2.64 (m, 2H), 3.67–3.81 (m, 1H), 4.42–4.55 (m, 1H), 6.19 (s, 2H), 7.31 (s, 1H), 7.34 (d, 1H, J=4.8), 7.43 (s, 1H), 7.52 (d, 1H, J=8.8), 7.76 (dd, 1H, J=2.6, 8.4), 7.87 (d, 1H, J=2.6), 8.53 (d, 1H, J=4.8); 13C NMR (CDCl3) δ 45.4, 46.6, 56.4, 97.9, 102.4, 106.6, 119.4, 122.3, 122.8, 124.6, 127.2, 134.0, 139.0, 144.5, 145.9, 148.1, 148.5, 149.6, 151.5, 166.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:16])[C:12](Cl)=[N:13][CH:14]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.[N:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([NH:26][CH2:25][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:13][CH:14]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(O)c2cccc(F)c2)cnc1Cl
Reactant: NCCCN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1c(C(O)c2cccc(F)c2)cnc1NCCCN1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of (3-fluoro-phenyl)-(2-chloro-3-methyl-3H-imidazol-4-yl)-methanol (1 equivalent) in THF (0.2 M) is added 3-piperidin-1-ylpropylamine (1.5 equivalents) and diisopropylethylamine (1.5 equivalents). The mixture is heated at reflux until HPLC analysis shows consumption of the starting material. The reaction mixture is cooled to rt, quenched with satd. aq. NH4Cl, and extracted with EtOAc (2×). The combined organic extracts are washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material is purified by chromatography or recrystallization to provide the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:11]([O:12][CH3:13])[CH2:10][C:9]2[C:8](=[NH:14])[NH:7][C:6](=N)[C:5]=2[CH2:4]1.Cl.[C:17]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N=C1C2CCCCC=2C(=N)N1>>[NH:14]=[C:8]1[C:9]2[CH2:10][CH:11]([O:12][CH3:13])[CH:3]([O:2][CH3:1])[CH2:4][C:5]=2[C:6](=[C:29]2[S:28][C:27]([NH:26][CH2:25][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:31][C:30]2=[NH:32])[NH:7]1
Reactant: N=C1CSC(NCCCc2ccccc2)=N1
Reactant: COC1CC2=C(CC1OC)C(=N)NC2=N
Agent: Cl
Agent: N=C1NC(=N)C2=C1CCCC2
Product: COC1CC2=C(CC1OC)C(=C1SC(NCCCc3ccccc3)=NC1=N)NC2=N

Procedure:
When equivalent amounts of 5,6-dimethoxy-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(3-phenylpropylamino)-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazoline hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-5,6-dimethoxy-4,5,6,7-tetrahydro-3-[2-(3-phenylpropylamino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2cccc(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 59% overall yield. FDMS m/e=426 (M+ of free base). α[D]589 =-11.39 (c=0.56, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:11]=[CH:10][C:8](=[O:9])O[CH:6]=1)=[O:4].[NH2:12][CH2:13][C@H:14]([OH:16])[CH3:15]>CO>[OH:16][C@H:14]([CH3:15])[CH2:13][N:12]1[C:8](=[O:9])[CH:10]=[CH:11][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6]1
Reactant: C[C@@H](O)CN
Reactant: COC(=O)c1ccc(=O)oc1
Solvent: CO
Product: COC(=O)c1ccc(=O)n(C[C@@H](C)O)c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of methyl coumalate (500 mg, 3.24 mmol) in MeOH (10 mL) was treated with (R)-(−)-1-amino-2-propanol (0.319 mL, 4.06 mmol) and TEA (0.790 mL, 5.68 mmol). The reaction was stirred at 23° C. under nitrogen. After 1 h, the reaction was concentrated and purified by silica gel chromatography (eluent: 55-95% EtOAc/hexane), affording (R)-methyl 1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate as a white solid. MS (ESI pos. ion) m/z: 212.1 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].C([O-])(=[O:46])C.C([OH:50])C.[ClH:51]>C(OCC)(=O)C>[CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:36][CH2:37]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].[OH2:46].[OH2:50].[OH2:20].[ClH:51]
Reactant: CC(=O)[O-]
Reactant: CCO
Agent: CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: Cl
Solvent: CCOC(C)=O
Product: O
Reaction time: 1 h

Procedure:
To a 16 L reactor was charged amorphous irinotecan acetate (234 g) and ethanol (1300 g). The reaction mixture was heated to reflux. 9N Hydrochloric acid (14.3 wt %, about 89 g) was added until the pH value of the solution was less than 4 in order to dissolve the solid particles. Ethyl acetate (2040 g) was added slowly to the mixture. The mixture was cooled to 0˜10° C. and stirred at this temperature for 1 hour. The solid particles were filtered and washed with cooled ethyl acetate (420 g). The wet cake was dried in vacuum to give 160 g of irinotecan hydrochloride trihydrate form IV.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][C:4](=O)[CH2:5][C:6]1[C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=1.O.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][C:4]1[N:21]=[N:20][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: CC(C)(C)CC(=O)CC1=CCCCCCC1=O
Reactant: NN
Agent: CC(C)(C)CC(=O)C/C1=C/CCCCCC1=O
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)Cc1cc2c(nn1)CCCCCC2
Temperature: 105 °C

Procedure:
A solution of (Z)-2-(4,4-Dimethyl-2-oxo-pentyl)-cyclooct-2-enone (0.07 g) in ethanol (6 ml) was treated at RT with water (1.5 ml), hydrazine monohydrate (0.07 ml) and acetic acid (1.5 ml), and the mixture was then heated to reflux for 12 h (oil bath temperature: 105° C.). The reaction mixture was partitioned between water and AcOEt. The combined organic layers were washed with 2M aqueous KHCO3, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100% to 85%) to give 3-(2,2-dimethyl-propyl)-5,6,7,8,9,10-hexahydro-cycloocta[c]pyridazine, (0.018 g) as an amorphous white solid. MS (ESI): 233.2 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:24])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Br)=[C:8]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[OH:23])[CH:7]=1>CN(C=O)C>[CH3:3][O:4][C:5]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]2[O:23][C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14][C:8]=2[CH:7]=1)=[O:24]
Reactant: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)SCc1cccc(Cl)c1O2
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Sodium hydride (1.65 g, 0.068 mol) was added portionwise to a solution of compound of Example 15a (23 g, 0.057 mol) in DMF (600 mL) and stirred at 80° C. for 10 h. The solvent was removed, and chloroform (300 mL) was added. The organic layer was washed with 10% HCl (2×80 mL), followed by water (100 mL), and brine and dried over anhydrous sodium sulphate. The solvent was removed and the crude product obtained was purified by column chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound. Yield: 9 g, (49%); 1H NMR (CDCl3, 300 MHz): δ 2.50 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.21 (s, 2H, CH2), 7.05 (m, 2H, Ar), 7.28 (d, 1H, Ar), 7.60 (d, 2H, Ar); MS: m/e (El) 320 (M+).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:19]([Cl:34])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:34][C:19]1[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Into a microwave vial was placed 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (79 mg, 0.00040 mol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (100 mg, 0.0003 mol) in isopropyl alcohol (4 mL, 0.05 mol) with 4N HCl-dioxane (0.04 g, 0.0003 mol). The reaction was subjected to microwaves at 120° C. for 10 min. HPLC and LCMS indicated trace starting material remaining. The reaction mixture was resubjected to microwaves for an additional 10 min. A tan solid had precipitated out of solution and was collected by filtration. The solid was redissolved in methylene chloride (5 mL) and washed with sat. sodium bicarbonate (1×5 mL) and water (2×5 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give N-{(1R,2R)-2-[5-Chloro-2-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a brown solid (75 mg, 40%). MP: 118-128° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.46 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz), 7.07 (d, 1H, J=8 Hz), 6.71 (d, 1H, J=8 Hz), 3.84 (m, 1H), 2.94 (s, 3H), 2.70 (m, 4H), 1.99-2.09 (m, 6H), 1.71 (m, 2H), 1.18-1.39 (m, 5H); MS (m/e) 500 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][CH2:2][CH2:3][NH2:4])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.1 %

Procedure:
1,2-Diaminoethane (7.55 mL, 113 mmol) was added to a 0° C. solution of 2,4-dichloro-3-nitroquinoline (28.9 g, 119 mmol) and triethylamine (24.9 mL, 179 mmol) in dichloromethane (600 mL). The solution was allowed to warm slowly to room temperature and stir for 20 hours. The solvent was removed under reduced pressure and 5% aqueous Na2CO3 (300 mL) was added. The resulting slurry was stirred vigorously at 0° C. for four hours. A yellow solid was isolated by vacuum filtration and dried under vacuum. The solid was purified by suction filter chromatography (silica gel, gradient elution from 98:2 to 93:7 dichloromethane/methanol) to provide the product N-(2-chloro-3-nitroquinolin-4-yl)ethane-1,2-diamine (16.0 g) that contained a small amount of an impurity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:5]2=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:7][NH:23][N:22]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2ccccc2F)coc2cc(O)c(Cl)cc12
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2F)cc1Cl
Yield: 72.4 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(2-fluoro-phenyl)-7-hydroxy-chromen-4-one (0.37 g, 1.27 mmol), hydrazine hydrate (5 ml), ethanol (15 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-chloro-6-[4-(2-fluoro-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.28 g, 72.4%); Rf 0.8 cf SM 0.9 ethyl acetate/hexane (70/30).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[O:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=O>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
4-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester (50 g, 169.3 mmol) is dissolved in 500 ml of ethyl acetate and DMAP (141 mg, 3.4 mmol) is added. Then the mixture is cooled to 0° C. and BOC2O (36.9 g, 169.3 mmol), dissolved in 20 ml of ethyl acetate, is added dropwise. After completion of addition the reaction mixture is allowed to stir over night at room temperature. The mixture is washed with 1M tartaric acid and brine. The organic layers are dried over sodium sulfate and evaporated
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[H-].[Na+].F[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[N:15][C:16]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)=[N:17]2)=[CH:12][CH:11]=1>C1COCC1>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[N:15][C:16]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([OH:27])[CH2:25][CH2:26]4)=[N:17]3)=[CH:12][CH:11]=2)[CH2:2]1
Reactant: OC1CCOC1
Reactant: O[C@H]1CC[C@H](Nc2ncc3ccc(F)cc3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](Nc2ncc3ccc(OC4CCOC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of tetrahydrofuran-3-ol (337 mg, 3.83 mmol) in THF (5 mL) was added NaH (153 mg, 60% disp. in oil, 3.83 mmol) and the mix stirred at r.t. for 20 min., forming a pale suspension. To this was added trans-4-[(7-fluoroquinazolin-2-yl)amino]cyclohexanol (100 mg, 0.383 mmol) and a yellow suspension formed almost immediately. The suspension was stirred at r.t. for 30 min then heated to 45° C. for 1 hour, then heated to 65° C. for 30 min then cooled to R.T. overnight. The liquors were concentrated and diluted with water (10 mL) and EtOAc (25 mL) and shaken vigorously. The aq. was removed and the organics washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and stripped to an oil. Purified by prep TLC eluting with EtOAc to yield the title compound as a white foam, 36 mg, 29%. 1H NMR (400 MHz, DICHLOROMETHANE-D2) δ ppm 8.75 (1H, s) 7.53 (1H, d, J=8.84 Hz) 6.62-6.88 (2H, m) 5.18 (1H, d, J=7.83 Hz) 5.05 (1H, s) 3.81-4.08 (5H, m) 3.54-3.79 (2H, m) 2.22-2.43 (1H, m) 2.08-2.21 (3H, m) 1.91-2.07 (2H, m) 1.36-1.51 (4H, m) 1.19-1.38 (4H, m); MS (API+) for C18H23N3O3 m/z 330.2 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][CH3:21])[CH2:3]1.C([BH3-])#N.[Na+].[CH3:26][C:27]([CH3:29])=O.[CH:30](=O)[CH3:31]>CO>[NH3:1].[CH2:30]([N:1]([CH:27]([CH3:29])[CH3:26])[C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:4]([CH2:19][O:20][CH3:21])[CH2:3]1)[CH3:31]
Reactant: COC[C@@H]1C[C@H](N)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CC(C)=O
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC)C1
Product: N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thetrifluoroacetic acid salt of benzyl (1S,2R,4R)-4-amino-2-(methoxymethyl)cyclohexylcarbamate (660 mg, assumed 1.68 mmol) was dissolved in methanol (5 mL) and treated with an excess of sodium cyanoborohydride (ca. 50-100 mg) and acetone (1 mL). The mixture was stirred overnight at rt, then treated with additional acetone and sodium cyanoborohydride. After 1 h, acetaldehyde (1 mL) was added, followed 4 h later by additional acetaldehyde and sodium cyanoborohydride. After stirring overnight at rt, additional acetaldehyde and sodium cyanoborohydride were added, followed by stirring for 3 days. The mixture was concentrated and the residue was dissolved in ethyl acetate and saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted four times with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated under vacuum. Purification by rotary preparative layer chromatography, eluting with 95:4:1 (v/v) dichloromethane:methanol:aqueous ammonia, provided benzyl (1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexylcarbamate (430 mg). MS found: (M+H)+=363.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH2:24])=[CH:7][N:6]=1)=[O:4].[C:25](OC(=O)C)(=[O:27])C>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:27])=[CH:7][N:6]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ncc(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: O=CO
Product: COC(=O)c1ncc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Yield: 98.3 %

Procedure:
A solution of 5-aminomethyl-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylic acid methyl ester (800 mg, 2.30 mmol) from above in formic acid (12 mL) and acetic anhydride (4 mL) was stirred at ambient temperature under N2 for 1.5 hour. The reaction mixture was concentrated in vacuo, and the residue was azeotroped with toluene. The resultant residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a yellow foam (850 mg, 98.3%). LCMS (method D1: RT=1.09 min, [M+H]+=377.