Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>CCO.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1cc(N)ccc1Cl
Yield: 560 %

Procedure:
Iron powder (2.5 g, 44.7 mmol) was added portion wise to a solution of ethyl 2-(2-chloro-5-nitrophenyl)acetate (8 g, 4.68 mmol) and cone. HCl (12 M, 3.9 mL, 46.8 mmol) in EtOH (100 mL). The resultant mixture was heated at 50° C. for 2 hour. The mixture was filtered and the filtrate cake was washed with saturated aqueous Na2CO3 until pH 8. The filter cake was further washed with EtOAc and the combined filtrates were partitioned between EtOAc and water. The organics were dried over Na2SO4 and concentrated in vacuo to provide ethyl 2-(5-amino-2-chlorophenyl)acetate (5.6 g, 56% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.00 (d, J=8.4 Hz, 1 H), 6.50 (s, J=2.8 Hz, 1 H), 6.44 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.20 (s, 2 H), 4.05 (q, J=7.2 Hz, 2 H), 3.56 (s, 2 H), 1.15 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Br:1]Br.ClC(Cl)C.[CH3:7][O:8][CH:9]([O:20][CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19].[OH-].[Na+]>CO>[Br:1][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH:9]([O:20][CH3:21])[O:8][CH3:7])=[C:13]([CH3:19])[C:14]=1[CH3:18]
Reactant: COC(COc1cccc(C)c1C)OC
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: COC(COc1ccc(Br)c(C)c1C)OC
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Bromine (140 g) was added dropwise to a 760 ml of dichloroethane solution containing 180 g of 1-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene while stirring and cooling (ice bath) and maintaining the temperature of the reaction mixture not exceeding 10° C. After stirring for 30 minutes after completion of the addition, the reaction mixture was condensed under reduced pressure (a temperature of 40° C. or lower). The condensate was added dropwise in a solution comprising 37 g of sodium hydroxide dissolved in 185 g of methanol while stirring. Stirring was continued for one hour after completion of the addition, methanol was removed under reduced pressure, and 30 ml of dichloroethane and 570 ml of water were added to the residue and then the mixture was separated with each other. The organic layer was condensed under reduced pressure, a resulting brownish oil was distilled under reduced pressure to give 228 g of 1-bromo-4-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene. Boiling point: 128° to 131° C./0.5 mmHg; Melting point: 40° to 41° C.; and Yield: 92%.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]#[CH:17])[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[C:21]2[C:34](=[CH:35][CH:36]=1)[CH2:33][C:23]1([C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]1=[O:32])[CH2:22]2.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.O.CCOC(C)=O.[Cu]I.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[Pd].[Pd]>[CH2:1]([N:8]([CH2:15][C:16]#[C:17][C:19]1[CH:20]=[C:21]2[C:34](=[CH:35][CH:36]=1)[CH2:33][C:23]1([C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]1=[O:32])[CH2:22]2)[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ncccc2C12Cc1ccc(Br)cc1C2
Reactant: C#CCN(Cc1ccccc1)C(=O)C(C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N(CC#Cc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21)Cc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a heterogeneous mixture of N-benzyl-2,2-dimethyl-N-prop-2-yn-1-ylpropanamide (222 mg, 0.968 mmol, from Step A), 5-bromo-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (218 mg, 0.692 mmol, described in Intermediate 5), CuI (7.0 mg, 0.35 mmol), tris(2-methylphenyl)phosphine (84.0 mg, 0.277 mmol) and triethylamine (0.6 mL), in DMF (0.8 mL), while under a nitrogen atmosphere, was added bis[tris(2-methylphenyl)phosphine]palladium (II) chloride (109 mg, 0.138 mmol). The reaction mixture was then heated to 50° C. for 20 hours. An additional amount of alkyne (2 drops), tris(2-methylphenyl)phosphine (40 mg) and palladium salt (50 mg) was added and the reaction was allowed to stir an additional 2 hours. The reaction was then diluted with water and EtOAc. The organics were separated and then washed with water (×5), then with brine (×1). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a residue. The residue was then applied to a silica gel column for partial purification, eluting with a gradient of 15-80% EtOAc in hexanes to give slightly impure title compound. This impure material was then applied to a silica gel column for purification, eluting with a gradient of 1-7% MeOH in DCM to give the title compound. MS: m/z=464 (M+1). Human CGRP receptor binding Ki=20 nM. HRMS: m/z=464.2346; calculated m/z=464.2333 for C30H30N3O2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[CH:16]([C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(C(=O)Nc1ccc(C(C)C)cc1)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.62 g), 4-isopropylaniline (0.41 g) and triethylamine (0.84 mL) were dissolved in DMF (20 mL), and HOBt.H2O (0.48 g) and WSCI.HCl (0.61 g) were added under ice-cooling. The mixture was stirred at room temperature for one day and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and ether was added to the residue. The precipitated solid was collected by filtration to give N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.70 g). melting point: 168-169° C.
Reaction SMILES: [C:1](=[O:27])([O:3][C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:17][C:16](=[O:18])[CH:15]=[C:14]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]3=2)[NH:7][C@@H:6]([CH3:26])[CH2:5]1)[NH2:2].N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:1](=[O:27])([O:3][C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:17][C:16](=[O:18])[CH:15]=[C:14]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]3=2)[N:7]([C:34](=[O:36])[CH3:35])[C@@H:6]([CH3:26])[CH2:5]1)[NH2:2]
Reactant: C[C@H]1C[C@@H](OC(N)=O)c2c(ccc3oc(=O)cc(Cc4ccccc4)c23)N1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc3oc(=O)cc(Cc4ccccc4)c3c2[C@H](OC(N)=O)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[Step 3] 226 mg of the cis-benzyl-8-methyl-3-oxo-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-10-yl carbamate and 0.15 mL of pyridine were dissolved in 10 of dichloromethane followed by adding 66 μL of acetyl chloride while cooling with ice and stirring for 1 hour at room temperature. Following completion of the reaction, the solution was concentrated under reduced pressure and saturated aqueous sodium bicarbonate solution was added to the resulting residue followed by extracting three times with chloroform. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 250 mg of cis-benzyl-7-acetyl-8-methyl-3-oxo-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-10-yl carbamate in the form of a yellow solid (99%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOCC>[Pd].CO>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH2:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(CN2CCCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
Add 4-(piperidin-1-ylmethyl)-benzonitrile (890 mg, 4.45 mmol), 2M hydrogen chloride in ether (8.9 mL, 17.8 mmol) and 10% Pd/C (90 mg) to methanol (100 mL) in a pressure vessel. Flush the vessel three times with hydrogen and charge to 50 psi with hydrogen. Stir at room temperature for 2 h. Filter the catalyst through Celite® and concentrate the filtrate in vacuo. Purify by chromatography on silica gel (100 g) eluting with a gradient of DCM to 4:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound as a colorless oil (0.82 g, 90%). MS (ES+) m/z: 205 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C@@H:8]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:9]([CH3:12])[CH2:10][OH:11].Br[CH2:23][C:24]([OH:26])=[O:25].[I-].[Na+]>C1COCC1>[C:16]([O:15][C:14]([N:13]([CH3:21])[C@H:8]([C:4]1[O:3][CH:7]=[CH:6][CH:5]=1)[C@H:9]([CH3:12])[CH2:10][O:11][CH2:23][C:24]([OH:26])=[O:25])=[O:20])([CH3:17])([CH3:19])[CH3:18]
Reactant: O=C(O)CBr
Reactant: C[C@H](CO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](COCC(=O)O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.7 %

Procedure:
To a suspension of NaH (60%, 134.0 mg, 3.4 mmol, 3.0 equiv) in THF (2.2 mL) at 0° C. was added 2.6.1a (300.0 mg, 1.1 mmol), bromoacetic acid (464.0 mg, 3.4 mmol, 3.0 equiv) and sodium iodide (167.0 mg, 1.1 mmol) successively. After stirring for 7 hours at room temperature, the reaction mixture was quenched with water at 0° C., diluted with EtOAc, and acidified with aqueous 1.0 N HCl aq. solution. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give [(2S,3S)-3-(tert-butoxycarbonyl methylamino)-3-furan-2-yl-2-methyl-propoxy]acetic acid (287.0 mg) which was used for the next step without further purification. MS m/z (M+Na) 350.0
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([OH:19])[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1.[H-].[Na+].O>O1CCOCC1>[O:15]1[C:16]2[CH:17]=[CH:18][C:10]([CH2:9][O:19][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=3)=[CH:11][C:12]=2[O:13][CH2:14]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cncc(OCc2ccc3c(c2)OCO3)n1
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 2,6-dichloropyrazine (298 mg, 2.00 mmol) and piperonyl alcohol (335 mg, 2.20 mmol) in dioxane (5 mL) was added NaH (55% in mineral oil, 96 mg, 2.2 mmol) at room temperature. The reaction mixture was stirred overnight. Water (0.5 mL) was added and the mixture was stirred for 15 min. Drying, Na2CO3, filtration and concentration in vacuo furnished an oil (0.54 g) that was used directly in the next step. HRMS m/z calcd for C12H9ClN2O3 (M)+ 264.0302, found 264.0303.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH3:25][C@H:26]([NH2:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C@@H:26]([NH:29][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)[CH3:25]
Reactant: COC(=O)c1ccc(OCc2c(C3CCOCC3)noc2C)nc1
Reactant: C[C@H](N)CO
Product: Cc1onc(C2CCOCC2)c1COc1ccc(C(=O)N[C@@H](C)CO)cn1
Temperature: 50 °C
Yield: 22.2 %

Procedure:
A mixture of 6-[5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.3 mol), S-(+)-2-amino-1-propanol (28.8 μL, 0.36 mmol) and TBD (12.8 mg, 0.09 mmol) was heated at 50° C. for 18 h under argon. The reaction mixture was concentrated onto silica then purified by chromatography (silica, 0 to 15% methanol in ethyl acetate) to give the title compound (30 mg, 27%) as a white solid. MS: m/e=374.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH:7]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:8](=[O:15])[NH:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[O:5].[CH:29](OCC)(OCC)OCC.CCN(CC)CC>>[CH:17]1([CH2:16][CH:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][CH:23]=3)[N:1]=[CH:29]2)[C:8]([NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cccc(C(=O)NC(CC2CCCCC2)C(=O)Nc2nccs2)c1N
Reactant: CCOC(OCC)OCC
Solvent: CCN(CC)CC
Product: COc1cccc2c(=O)n(C(CC3CCCCC3)C(=O)Nc3nccs3)cnc12
Temperature: 130 °C

Procedure:
2-amino-N-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-methoxybenzamide (0.5 g, 1.24 mmol) was dissolved in (EtO)3CH:Et3N (4:1, 2 mL) and the reaction was heated to 130° C. overnight. All solvents were removed. The crude product was purified via preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.31 (m, 6H) 1.54-1.77 (m, 4H) 1.85 (s, 1H) 2.05-2.18 (m, 1H) 2.23-2.36 (m, 1H) 4.04 (s, 3H) 5.68-5.80 (m, 1H) 7.13 (d, J=4.29 Hz, 1H) 7.30 (d, J=8.08 Hz, 1H) 7.45-7.59 (m, 2H) 7.85 (d, J=8.08 Hz, 1H) 8.60 (s, 1H). [M+H] calc'd for C21H24N4O3S, 413; found, 413.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CC#N>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(S(C)(=O)=O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (60 mg, 0.16 mmol) in MeCN (1.5 mL) was added triethylamine (64 uL, 0.47 mmol) and methane sulfonyl chloride (36 uL, 0.47 mmol). The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the product isolated by Prep HPLC (low pH) as an off white/pink solid (36 mg, 0.078 mmol, 49% yield).
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:36])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)C>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][CH:24]([CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6][C:5]1=[O:36])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCC(CCCN5CCOCC5)CC4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)n1c(=O)ncc2cnc(Nc3ccc(N4CCC(CCCN5CCOCC5)CC4)cc3)nc21
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Prepared from 100 mg (0.20 mmol) of 1-isopropyl-7-{4-[4-(3-(morpholin-4-yl)propyl)piperidin-1-yl]phenylamino}-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 88.5 mg (0.79 mmol) of potassium tert-butoxide in 10 mL of tetrahydrofuran. The reaction mixture is stirred overnight, 88.5 mg (0.79 mmol) of potassium tert-butoxide is added, and the reaction is continued for 48 hours. After the workup, the semi-solid is five times suspended in diethyl ether and rotovapped to dryness to give 87 mg (85%) of the title compound: mp>95° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([C:9]2[CH:37]=[CH:36][C:12]3[N:13]([CH2:17][CH2:18][O:19][C:20]4[CH:35]=[CH:34][C:23]([CH2:24][CH:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=4)[C:14](=[O:16])[S:15][C:11]=3[CH:10]=2)=O)=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[CH:37]=[CH:36][C:12]3[N:13]([CH2:17][CH2:18][O:19][C:20]4[CH:35]=[CH:34][C:23]([CH2:24][CH:25]([C:26]([O:28][CH3:29])=[O:27])[C:30]([O:32][CH3:33])=[O:31])=[CH:22][CH:21]=4)[C:14](=[O:16])[S:15][C:11]=3[CH:10]=2)=[CH:38][CH:39]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccc(OC)cc4)ccc32)cc1)C(=O)OC
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(Cc4ccc(OC)cc4)ccc32)cc1)C(=O)OC

Procedure:
The procedure is as in Example 48, starting from the compound obtained in Example 61. The recrystallisation solvent is methanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].ClS([N:33]=[C:34]=[O:35])(=O)=O.O.C(OCC)(=O)C.CCCCCC>C1C=CC=CC=1>[NH2:33][C:34]([O:1][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:35]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
2-Hydroxymethyl-6-methyl-4-(nitrophenyl)-3,5-diethoxycarbonyl-1,4-dihydropyridine (390 mg) was dissolved in benzene (10 ml), chlorosulfonyl isocyanate (0.2 ml) was added thereto, and the mixture was reacted under stirring at room temperature for 30 minutes. Water (10 ml) was added to the reaction mixture under cooling, and the mixture was stirred at room temperature for 30 minutes for hydrolysis. The reaction mixture thereby obtained was extracted with ethyl acetate, and the extracted solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane, whereupon crystals (210 mg, yield: 48.5%) were obtained.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ncccc12
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a mixture of methyl 4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}benzoate (975 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), 1N hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (701 mg, 75%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14]([CH2:15][C@@H:16]([O:24][Si](C(C)C)(C(C)C)C(C)C)[CH2:17][CH2:18]1)=[N:13][CH2:12]3)([O:3][CH3:4])=[O:2].[C:35]([O:39][C:40](OC(OC(C)(C)C)=O)=[O:41])([CH3:38])([CH3:37])[CH3:36].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1.O1CCCC1.O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[N:13]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN=C4C[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(=O)OC(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
A portion of the crude product from above, 17β-carbomethoxy-3β-triisopropylsilyloxy-6-azaandrost-5-ene (66 g, 0.135 mol) is dissolved in pyridine (500 mL), treated with di-t-butyldicarbonate (150 g, 0.69 mol) and allowed to stir overnight. The pyridine is removed by rotary evaporation and tetrabutylammonium fluoride (500 mL, 1M, 0.5 mol) in tetrahydrofuran (THF) added carefully and the reaction heated to reflux for 5 min. The THF is removed by rotary evaporation, the residue dissolved in ethyl acetate (500 mL), washed cautiously with water, saturated aqueous NaCl, dried with MgSO4 and concentrated. This material is dissolved in DMF (500 mL), is treated with pyridinium dichromate (153 g, 0.41 mol) and allowed to stir overnight. The reaction is poured into water (700 mL) and extracted with ethyl acetate (2×500 mL). The combined extracts are washed with water, 5% aqueous CuSO4, saturated aqueous NaCl, dried over MgSO4, concentrated and flash chromatographed (0-60%, diethyl ether/hexanes) to give 17β-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one as an off-white foam; yield: 37.5 g (64%); FAB mass spec. MH+ 432.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C@H:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[C:6](=[O:13])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:21]>CCOC(C)=O.O1CCOCC1>[ClH:21].[CH3:1][CH:2]1[N:7]([C@H:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[C:6](=[O:13])[CH2:5][NH:4][CH2:3]1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1[C@H]1CCOC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1CNCC(=O)N1[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude II2 was dissolved in EtOAc, then 4M HCl in dioxane was added. The mixture was stirred at RT for 30 min. After the removal of the solvent under reduced pressure, the crude was scratched with Et2O and the solvent decanted to afford the title compound (II3). MS (ES) C9H17ClN2O2 requires: 184, found: 185 (M+H)+.