Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[C:8]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH3:20])[N:9]=1>C(Cl)Cl>[F:22][C:7]([F:6])([F:21])[C:8]1[N:12]=[CH:11][N:10]([C:13]2[C:14]([CH3:20])=[CH:15][C:16]([CH3:19])=[C:17]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:18]=2)[N:9]=1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)(F)F)n1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 5 g of chlorosulphonic acid are introduced and are admixed at room temperature, in portions, with 3.6 g of 3-(trifluoromethyl)-1-(2,4-dimethylphenyl)-1H-1,2,4-triazole. The exothermic reaction raises the temperature of the mixture to around 45° C. The mixture is subsequently stirred at 70° C. for 3 hours and then cooled, and diluted with 20 ml of methylene chloride. The mixture is added with stirring to ice and then the phases are separated and washed with twice 20 ml of methylene chloride. The combined organic phases are concentrated on a rotary evaporator and then chromatographed (CH2Cl2). This gives 3.8 g of solid (76% of theory). This solid is reacted further directly.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]#[N:5].[F:6][C:7]1([F:23])[CH2:10][CH:9]([C:11](OCC2C=CC(OC)=CC=2)=[O:12])[CH2:8]1.O>O1CCOCC1>[F:6][C:7]1([F:23])[CH2:10][CH:9]([C:11](=[O:12])[CH2:3][C:4]#[N:5])[CH2:8]1
Reactant: CC#N
Reactant: COc1ccc(COC(=O)C2CC(F)(F)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCC(=O)C1CC(F)(F)C1
Reaction time: 0.33 h
Yield: 155.1 %

Procedure:
To a solution of NaH (2.85 g, 71.1 mmol) in dioxane (200 mL) was added MeCN (2.92 g. 71.1 mmol). The mixture was stirred for 20 min, then the solution of 4-methoxybenzyl 3,3-difluorocyclobutanecarboxylate (14.0 g, 54.7 mmol) in dioxane (100 mL) was added dropwise. After the mixture was heated at reflux for 4 h, the reaction mixture was poured into water (400 mL) then extracted with EtOAc (200 mL). The pH of the aqueous layer adjusted to 7 with 3N HCl and extracted with EtOAc. The organic layer was washed with brine (200 mL), dried (Na2SO4), filtered and concentrated to afford 13.5 g crude 3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCN3CCN(C)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(4-chloro-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 255) and 1-methyl-piperazine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C26H39N7O4SF [(M+H)+]564.2767, observed 564.2763.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH:22]([CH2:29][CH3:30])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[C:18]([O:19][CH2:30][CH2:29][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)CC(Br)CC
Reactant: CCCCCCOc1c(O)c2cccc(O)c2oc1=O
Product: CCCCCCOc1c(O)c2cccc(OCCCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-hexyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopentanoate was used in place of ethyl bromoacetate in Reference Example 3, 3-hexyloxy-4-hydroxy-8-(4-ethoxycarbonylbutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH3:19])[N:8]=[N:9]2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:20][C:6]1[C:5]2[C:10](=[CH:11][C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[CH:3][CH:4]=2)[N:9]=[N:8][C:7]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1CCc1nnc2cc(Br)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1CCc1nnc2cc(-c3ccc(C#N)cc3)ccc2c1O
Temperature: 90 °C
Yield: 33 %

Procedure:
A mixture of the product from Example 168D (0.30 g, 0.805 mmol), 4-cyanophenylboronic acid (0.15 g, 1.05 mmol), Pd(PPh3)2Cl2 (0.03 g, 0.04 mmol), and 1 M Na2CO3 (2.01 mL, 2.01 mmol) in isopropanol (15 mL) was heated to 90° C. under a dry nitrogen atmosphere for 2 days. After cooling, the reaction mixture was filtered through celite and concentrated under reduced pressure. The crude material was purified by column chromatography (100% dichloromethane to 90:10 dichloromethane/methanol) to afford the product in 33% yield as a light brown solid. 1H NMR (CD3OD, 300 MHz) δ 8.29 (d, J=9 Hz, 1H), 7.95 (q, J=9 Hz, 4H), 7.83 (d, J=3 Hz, 1H), 7.75 (dd, J=3, 9 Hz, 1H), 3.49-3.42 (m, 2H), 3.17-3.12 (m, 2H), 2.78-2.73 (m, 2H), 2.62-2.59 (m, 1H), 2.12-2.09 (m, 1H), 1.92-1.84 (m, 2H), 1.61-1.53 (m, 1H), 1.25 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 359.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:48])[CH2:33][C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[CH:44][C:43]([CH:46]=O)=[CH:42][CH:41]=2)[CH:37]=[CH:38][CH:39]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:46][C:43]3[CH:44]=[CH:45][C:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([CH2:33][C:32]([OH:48])=[O:31])[CH:35]=4)=[CH:41][CH:42]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)Cc1cccc(-c2ccc(C=O)cc2)c1
Product: O=C(O)Cc1cccc(-c2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and (4′-formylbiphenyl-3-yl)-acetic acid methyl ester. MS (ESI) m/z 615.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[N-:22]=[N+:23]=[N-:24].[Li+]>CN1CCCC1=O.O>[N:22]([CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(CN=[N+]=[N-])nc2c(N)nc3ccccc3c21

Procedure:
2-Chloromethyl-1 (2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (2.5 g; 0.0077 mol, Example 10) was suspended in N-methylpyrrolidone (15 mL). A solution of lithium azide (2.3 g) in water (45 mL) was added to the suspension. The resulting mixture was heated on the steam bath for 2 hr and then diluted with water (about 45 mL). The tan solid was washed with water and dried to yield 1.4 g (60.9%) of crude product. The solid was recrystallized from ethanol to give a pure product m.p. 174-178° C. Analysis: C, 61.0; H, 5.8; N, 33.2. Found: C, 60.9; H, 5.6; N, 32.6.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:34]>C1COCC1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][O:26][CH3:34])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)COC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 50 mg (0.112 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in 0.5 mL of THF was added 60% sodium hydride (8.96 mg, 0.244 mmol) at 0° C. After being stirred at 0° C. for 30 min, iodomethane (14.01 uL, 0.244 mmol) was added. The reaction was allowed to warm to 25° C., and stirred for an additional 2 h until completion. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[N-:23]=[N+]=[N-].[Na+].O.[OH-].[Na+]>Cl>[O:1]=[C:2]1[NH:23][CH2:7][CH2:6][CH:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]2)=[O:10])[CH2:4][CH2:3]1
Reactant: O=C1CCC(NC(=O)[C@H]2CCCN(c3ccccc3)C2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCC(NC(=O)[C@H]2CCCN(c3ccccc3)C2)CCN1
Temperature: 50 °C

Procedure:
To a solution of (3S)-N-(4-oxocyclohexyl)-1-phenylpiperidine-3-carboxamide (10 mg, 0.00003 mol, prepared as example 171) in concentrated aqueous HCl (0.5 mL), was added sodium azide (2.27 mg, 0.0000350 mol) in small portions over 3 minutes with slow agitation. The temperature was slowly increased to 50° C. The reaction temperature was maintained at 50° C. for 8.5 h and then poured into 50 g of crushed ice and water. The solution was basified with cold 50% NaOH and the resulting solution was extracted with EtOAc(×3). The EtOAc extracts were combined, dried over MgSO4, filtered and evaporated to yield the crude product, which was purified by prep-HPLC. LCMS: (M+H)+=316.2.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([OH:16])[CH2:14][OH:15].C(OCC)(OCC)OCC>C([O-])(O)=O.[Na+]>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: OCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: COC(=O)c1ccc(C2OCCO2)cc1
Reaction time: 0.08 h

Procedure:
Methyl 4-formylbenzoate (3.28 g, 20.0 mmol) was suspended in ethylene glycol (4.46 mL, 80.0 mmol), then successively treated with triethyl orthoformate (3.66 mL, 22.0 mmol) and Me3NPhBr3 (376 mg, 1.00 mmol) at 22° C.; within 5 min, all solids dissolved. The resulting orange solution was stirred 0.5 h, then diluted with saturated aqueous NaHCO3 (50 mL), transferred to separatory funnel and washed with EtOAc (3×50 mL). The combined EtOAc washes were dried over MgSO4, filtered and concentrated in vacuo to a colorless oil (Rf 0.4 in 4:1 pentane/EtOAc, KMnO4). This material was used without further purification in the subsequent reduction step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14]I.O>CN(C)C=O>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 48 h
Yield: 90.6 %

Procedure:
To solution of 4-bromo-2-nitro-benzoic acid (9 g, 36.58 mmol) in dimethylformamide (36 mL) cooled to 0° C. were added 1,8-diazabicyclo[5.4.0]und-7-ene (28.09 mL, 182.9 mmol) and MeI (11.4 mL, 182.5 mmol). The reaction mixture was stirred at 0° C. for 15 min and at r.t. for 48 h. The mixture was poured into water and extracted with EtOAc (2×). The combined organic phases were washed with water (2×), dried (Na2SO4) and concentrated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to give 4-bromo-2-nitro-benzoic acid methyl ester (8.62 g, 33.147 mmol, 90%). 1H-NMR (CDCl3, 400 MHz) 8.02 (s, 1 H), 7.81 (dd, J=2.3, 10.5 Hz 1H), 7.66 (d, J=8.2 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[O-:13]C1C=CC=CC=1.[K+].O>C(O)COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:13]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: [O-]c1ccccc1
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Temperature: 160 °C

Procedure:
3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160° C. for approximately 15 hours. The resulting dark brown solution is cooled to room temperature, poured onto 100 mL cold water, and extracted twice with diethyl ether. The pooled organic extracts are washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:12]1([C:18]2[N:19]=[C:20]([CH2:25][C:26]([O-])=[O:27])[NH:21][C:22](=[O:24])[CH:23]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[Na+].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[CH3:3][C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:26](=[O:27])[CH2:25][C:20]2[NH:21][C:22](=[O:24])[CH:23]=[C:18]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:19]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
224 mg of 3-(tert-butyl)aniline are added to a solution of 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 in 10 ml of methanol. The reaction mixture is stirred at ambient temperature for 5 minutes and then 442 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride hydrate are added. The resulting mixture is thus stirred for 30 minutes at ambient temperature. The reaction mixture is concentrated under reduced pressure. The evaporation residue is taken up with 10 ml of water and 10 ml of ethyl acetate. The resulting product is then stirred for 30 minutes. The precipitate formed is filtered off. 235 mg of N-[3-(2-methylpropan-2-yl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CCO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:31]([C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1)#N>>[OH:2][CH2:1][CH2:31][C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1
Reactant: C[C@]12CCCCC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 100 %

Procedure:
The title compound II-al was prepared in 100% yield from 3,3:17,17-bis(ethylendioxy)-6α-(2-hydroxyethyl)androstane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, dmso-d6, ppm from TMS): δ 4.32 (t, 1H), 3.39 (m, 2H), 2.46-0.54 (m, 23H), 0.98 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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:13]1([NH:12][C:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]4[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=4[CH3:30])[C:23]([NH:22][CH:19]4[CH2:20][CH2:21]4)=[O:40])=[CH:11][CH:10]=3)[CH:5]=[N:6][N:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1ccc2c(NC3CCCCC3)nncc2c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(NC3CCCCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
The mixture of 6-bromo-N-cyclohexylphthalazin-1-amine (0.2 g, 0.65 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.2 g, 0.65 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.0325 mmol) and 2M potassium carbonate (1 mL, 1.95 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. (Product MS found to be M+1=401). The mixture was transferred directly to a column and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.17 g) as a yellow solid. Found MS (ES+): 401(M+H)+.
Reaction SMILES: C(O)(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.O1CC[CH2:16]OO1>OS(O)(=O)=O.O=S(=O)=O>[C:6]1([C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[CH2:16][O:8]1)=[O:7]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1COOOC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C1OCc2ccccc21
Temperature: 145 °C

Procedure:
Terephthalic acid was suspended in 25-30% oleum. Trioxane was added and the mixture was heated to 140-150° C. for 4-8 hours. The reaction mixture was cooled and then quenched by cautious addition of water at less than 80° C. The resulting suspension was cooled to about 40° C. and the solid was filtered off. The filter cake was washed with water followed by propan-2-ol before slurrying the solid in propan-2-ol at reflux for 30 minutes. After cooling to 20-25° C. the product was filtered off, washed with propan-2-ol and dried at 60-70° C. under reduced pressure.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:44][CH2:43][C:29]2([O:34][CH:33]([C:35](O)=[O:36])[CH2:32][N:31]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.[NH2:46][CH2:47][C:48](=[O:50])[CH3:49].CCN(CC)CC>CC1CCCO1>[CH2:47]([NH:46][C:35]([CH:33]1[O:34][C:29]2([CH2:43][CH2:44][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]2)[CH2:30][N:31]([CH2:38][C:39]([F:41])([F:40])[F:42])[CH2:32]1)=[O:36])[C:48]([CH3:49])=[O:50]
Reactant: CC(=O)CN
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(C(=O)O)O2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: CC(=O)CNC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 45 °C
Yield: 49.4 %

Procedure:
T3P (591 mg, 553 μL of 50% w/w, 0.93 mmol) was added to a mixture of 9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (142 mg, 0.37 mmol), 1-aminopropan-2-one hydrochloride salt (41 mg, 0.37 mmol) and Et3N (188 mg, 259 μL, 1.86 mmol) in 2-methyltetrahydrofuran (706 μL). The reaction mixture was then heated at 45° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 0-50% EtOAC in DCM as eluent to afford tert-butyl 10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 49%) as a yellow solid. ESI-MS m/z calc. 437.5. Found 438.7 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:29][C:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)([OH:27])[CH3:28])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC1(c2ccc(Cl)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(n(CC(C)(O)c3ccc(Cl)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.852 mmol) was added and stirred at RT for 5 min. 2-(4-Chlorophenyl)-2-methyloxirane (214 mg, 1.27 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 150 mg of (1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-chlorophenyl)propan-2-ol) as the TFA salt.