Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>O>[C:25]([NH:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH3:18])(=[O:27])[CH3:26]
Reactant: CC(CCN)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC(C)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
A mixture of 2.6 g of of 3-(4'-chloro-4-biphenylyl)butylamine, 12 ml of pyridine and 1 ml of acetyl chloride is allowed to stand for 2 hours, decomposed with water and worked up in the customary manner to give 1-acetamido-3-(4'-chloro-4-biphenylyl)-butane, m.p. 118°-120°.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]([CH2:9][CH2:10][CH2:11][CH:12]=O)=[N:8][C:4]=2[CH:3]=1.[CH3:25][C:26]1([CH3:52])[O:30][C@@H:29]2[C@@H:31]([CH2:47][NH:48][CH:49]([CH3:51])[CH3:50])[CH2:32][C@@H:33]([N:34]3[C:38]4[N:39]=[CH:40][N:41]=[C:42]([NH:43][CH:44]5[CH2:46][CH2:45]5)[C:37]=4[CH:36]=[CH:35]3)[C@@H:28]2[O:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:48]([CH2:47][C@@H:31]3[C@H:29]4[O:30][C:26]([CH3:52])([CH3:25])[O:27][C@H:28]4[C@H:33]([N:34]4[C:38]5[N:39]=[CH:40][N:41]=[C:42]([NH:43][CH:44]6[CH2:46][CH2:45]6)[C:37]=5[CH:36]=[CH:35]4)[CH2:32]3)[CH:49]([CH3:50])[CH3:51])=[N:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(Cl)c(Cl)cc21
Reactant: CC(C)NC[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)N(CCCCc1nc2cc(Cl)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 0.25 h
Yield: 74 %

Procedure:
4-(5,6-Dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)butanal (0.285 g, 0.735 mmol) and 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-[(propan-2-ylamino)methyl]-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.270 g, 0.700 mmol) were dissolved in DCE (17 ml) at r.t. under N2 and left for 15 mins. Sodium triacetoxyborohydride (0.208 g, 0.981 mmol) was added and the reaction left overnight. The reaction was quenched by the addition of sat. Na2CO3 solution (20 ml) and DCM (20 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography using between 100% DCM to 15% MeOH:85% DCM as eluent to give the product as a white foam (0.392 g, 74%): MS (ESI+) for C38H55Cl2N7O3Si m/z 379.2 [M+H]2+, 756.4 [M+H]+; LC purity 100% (ret. time, 1.76 min); 1H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 6.98 (d, J=3.63 Hz, 1H), 6.63 (br. s., 1H), 5.47 (br. s., 1H), 5.40 (s, 2H), 4.86-5.04 (m, 2H), 4.47 (br. s., 1H), 3.45-3.56 (m, 2H), 2.94-3.04 (m, 2H), 2.91 (t, J=7.72 Hz, 2H), 2.67 (br. s., 1H), 2.24-2.59 (m, 5H), 2.03 (br. s., 1H), 1.82-1.95 (m, 2H), 1.59 (br. s., 2H), 1.55 (s, 3H), 1.28 (s, 3H), 0.99 (br. s., 5H), 0.84-0.96 (m, 5H), 0.65-0.74 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:16])[NH:7][C:8]([NH:12][N+]([O-])=O)=[N:9][C:10]=1[CH3:11])[CH:2]([CH3:4])[CH3:3].[C:17](O)(=O)[CH3:18].C(N)C>O>[CH2:17]([NH:12][C:8]1[NH:7][C:6](=[O:16])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([CH3:11])[N:9]=1)[CH3:18]
Reactant: CC(=O)O
Reactant: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1CC(C)C
Agent: CCN
Solvent: O
Product: CCNc1nc(C)c(CC(C)C)c(=O)[nH]1
Temperature: 120 °C

Procedure:
5-Isobutyl-6-methyl-2-nitraminopyrimid-4(3H)-one (16.0 g) was mixed with ethylamine acetate (30 g) and heated without solvent at 120° C for 6 hours. The melt was cooled and water was added. The mixture was brought to pH 5 and the precipitated product recrystallised from aqueous acetone to give 2-ethylamino-5-isobutyl-6-methylpyrimid-4(3H)-one (formula VII, R1 = CH3, R = is C4H9, R6 = H, R7 = C2H5) having a melting point of 203°-204° C.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:25]=[C:26]([O:28][C@H:29]4[CH2:33][CH2:32][N:31]([CH3:34])[C:30]4=[O:35])[CH:27]=3)[C:15]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>[Pd].C1COCC1.C(O)C>[N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:25]=[C:26]([O:28][C@H:29]4[CH2:33][CH2:32][N:31]([CH3:34])[C:30]4=[O:35])[CH:27]=3)[C:15]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 88.8 %

Procedure:
A solution of 3-[4-(azetidine-1-carbonyl)-2-chloro-phenoxy]-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 22) (120 mg, 0.22 mmol) and 10% palladium on carbon (20 mg, catalytic) in THF (5 mL) and ethanol (5 mL) was stirred under an atmosphere of hydrogen for 16 hours. The palladium on carbon was removed by filtration and the filtrate evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated under reduced pressure to give product (98 mg, 89%). 1H NMR δ (300 MHz, CDCl3) 2.12-2.26 (m, 1H), 2.36 (quintet, 2H), 2.52-2.67 (m, 4H), 2.94 (s, 3H), 3.35-3.57 (m, 2H), 4.19-4.42 (m, 4H), 4.93 (t, 1H), 6.93 (s, 1H), 7.03 (d, 2H), 7.20 (s, 1H), 7.42 (s, 1H), 7.66 (d, 2H), 8.15 (s, 1H), 8.54 (s, 1H), 9.52 (s, 1H); m/z 502 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[S:10]1[C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=5)[CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9]1
Reactant: BrCCc1ccc2ncsc2c1
Reactant: COc1ccc2c(c1)N(C1CCNCC1)CC2
Product: COc1ccc2c(c1)N(C1CCN(CCc3ccc4ncsc4c3)CC1)CC2
Yield: 82.6 %

Procedure:
6-(2-Bromoethyl)benzothiazole (0.108 g) and 1-(piperidin-4-yl)-6-methoxyindoline (0.105 g) were treated as in Example 2 to give the title compound (0.145 g) as a yellow oil (yield: 81.9%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.Cl.[CH3:16][N:17]1[C:21](=[O:22])[C:20]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:16][N:17]1[C:21](=[O:22])[C:20]2([CH2:23][CH2:24][N:25]([C:2]3[N:3]=[N:4][C:5]([C:8]4[S:12][N:11]=[C:10]([CH3:13])[N:9]=4)=[CH:6][CH:7]=3)[CH2:26][CH2:27]2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)C(=O)N(C)CN4c3ccccc3)nn2)n1

Procedure:
The object product (85 mg, 33%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (130 mg), 3-methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one dihydrochloride (223 mg) and potassium carbonate (130 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7](Br)[CH:6]=1.[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1B(O)O)=[O:15]>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:6]=[C:7]([C:21]2[CH:20]=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][C:16]=2[CH:14]=[O:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: COc1ccc(C=O)c(B(O)O)c1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: COC(=O)Cc1cc(Cl)cc(-c2cc(OC)ccc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-5-chloro-phenyl)-acetic acid methyl ester and 2-formyl-5-methoxyphenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].Cl.[CH2:35]([N:37]([CH2:40][CH2:41]Cl)[CH2:38][CH3:39])[CH3:36]>>[CH2:35]([N:37]([CH2:40][CH2:41][O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH2:38][CH3:39])[CH3:36]
Reactant: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)C(=O)O
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 2-[(N,N-diethyl)amino]ethyl ester was prepared from N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine and 2-[(N,N-diethyl)aminoethyl chloride hydrochloride using the general procedure described in example 28 and was obtained as an amorphous white solid. ES-HRMS m/e calcd for C30H37ClN4O5 (M+H) 569.2525, found 569.2530.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:26][CH:27]=1)#[N:2]
Reactant: O=Cc1cccnc1
Reactant: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CNCC(C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(Cc3cccnc3)CC(C1)O2
Reaction time: 1.5 h
Yield: 68 %

Procedure:
N-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]methanesulfonamide (79 mg, 0.2 mmol; see Example 3(ii) above) and pyridine-3-carbaldehyde (36 mg, 0.34 mmol) were dissolved in DCM (4 mL) and shaken for 1.5 h. Sodium triacetoxyborohydride (144 mg, 0.68 mmol) was added and the mixture was shaken overnight. The reaction was quenched with 1 M K2CO3 (2 mL) and was then phase-separated. The aqueous layer was washed with DCM (3×3 mL) and the organic layers were combined and evaporated. The residue was purified by chromatography on silica, which gave 66 mg (68%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:10])[NH:8][CH3:9])=[C:5]([NH:11][C:12]([C:14]2[C:19](Br)=[CH:18][N:17]=[C:16]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[N:15]=2)=[O:13])[CH:4]=[N:3]1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1>>[CH3:1][N:2]1[C:6]([C:7](=[O:10])[NH:8][CH3:9])=[C:5]([NH:11][C:12]([C:14]2[C:19]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:18][N:17]=[C:16]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[N:15]=2)=[O:13])[CH:4]=[N:3]1
Reactant: Nc1cncnc1
Reactant: CNC(=O)c1c(NC(=O)c2nc(C3CCC3)ncc2Br)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(C3CCC3)ncc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 5-bromo-2-cyclobutyl-pyrimidine-4-carboxylic acid (1-methyl-5-methylcarbamoyl-1H-pyrazol-4-yl)-amide (23 mg, 58 μmol) and 5-aminopyrimidine (8 mg, 82 μmol) according to the method described in example A-1, step 2 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (1 mg, 5%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21](=[N:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=4[O:35][CH3:36])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:39]=[C:40]([C:45]([O:47]C)=O)[C:41]([O:43][CH3:44])=[O:42]>O(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21]4[N:25]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=5[O:35][CH3:36])[C:45](=[O:47])[C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][C:22]=4[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CCCC(=NCc1ccc(OC)cc1OC)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 24.6 %

Procedure:
A solution of 4 N-(1-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)butylidene)-1-(2,4-dimethoxyphenyl)methanamine (5.7 g, 11.2 mmol) and dimethyl 2-(methoxymethylene)malonate (2.55 g. 14.4 mmol) in Ph2O (10 mL) was heated at 220° C. for 30 min. The reaction mixture was then cooled to room temperature and loaded directly on silica gel eluting with hexanes/EtOAc (9:1) to afford the title compound as an orange foam (1.7 g, 25%).
Reaction SMILES: [OH:1][C@H:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:18])[CH3:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:16][C:15]([CH3:17])=[C:10]([N:6]1[C@H:7]([S:8][CH3:9])[C@@H:4]([C@@H:2]([O:1][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH3:3])[C:5]1=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O)[C@H]1SC
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of methyl 2-[(3S,4R)-3-{(1S)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (376 mg) and 4-dimethylaminopyridine (336 mg) in dichloromethane (3 ml) was added p-nitrobenzyl chloroformate (358 mg) at -30° C. under a nitrogen atmosphere. After stirring for one hour at 0° C., the mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid, water, a dilute aqueous sodium bicarbonate, and brine. Drying over magnesium sulfate and the removal of the solvent left an oil (635 mg), which was chromatographed on silica gel (25 g) eluting with 10-25% ethyl acetate in hexane to afford methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate (566 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[N:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2cccnc2c1NCC1(O)CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A solution of 1-{[(3-amino[1,5]naphthyridin-4-yl)amino]methyl}cyclohexanol (prepared as described in Part B, 15.1 mmol), trimethyl orthobutyrate (2.63 mL, 16.6 mmol), and pyridine hydrochloride (0.650 g, 5.64 mmol) in toluene (100 mL) was heated at reflux overnight. The solution was allowed to cool to rt, then was concentrated under reduced pressure. The residue was partitioned between chloroform (200 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with chloroform (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate and isolated by filtration. The filtrate was concentrated and the solid was again triturated with ethyl acetate; this procedure was repeated two more times. The white solids were combined and dried under vacuum to yield 1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (3.40 g, 70% over two steps).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]([OH:16])[CH3:15])=[CH:13][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:6][CH2:5][C:4]1=[O:24])[CH3:2].CN(C)C1C=CC=CC=1.[CH3:34][O:35][CH2:36]Cl.Cl>>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]([O:16][CH2:34][O:35][CH3:36])[CH3:15])=[CH:13][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:6][CH2:5][C:4]1=[O:24])[CH3:2]
Reactant: COCCl
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)O)ccc21
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)OCOC)ccc21
Reaction time: 96 h

Procedure:
A mixture of 3 g (9.2 mmol) of 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-(1-hydroxyethyl)-2H-1,4-benzodiazepin-2-one, 4.7 ml of dimethylaniline and 1.4 ml of chlorodimethyl ether is left to stand under argon at 50° for 1 hour and at room temperature for 4 days. The mixture is made acid at 0° C. with 1 N hydrochloric acid, extracted with chloroform/ethanol (9:1) and the organic phase is washed with water. After drying and evaporating, the residue is chromatographed on 100 g of silica gel using chloroform as the elution agent. There is obtained 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-[1-(methoxymethoxy)ethyl]-2H-1,4-benzodiazepin-2-one as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:3]=1.[I:17]I>C(#N)C>[I:17][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:5]=1[CH3:7]
Reactant: Cc1cc(C)n(-c2ccc(CCO)cc2)n1
Reactant: II
Solvent: CC#N
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Yield: 129.4 %

Procedure:
A mixture of 2-[4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 1, 1.26 g, 5.8 mmol), iodine (883 mg, 3.5, mmol) and ceric ammonium nitrate (1.59 g, 2.9 mmol) was stirred in acetonitrile (58 mL) at room temperature for 1 h. Then, the solvent was evaporated under reduced pressure and the resulting residue was dissolved dichloromethane. The organic solution was washed with 5% aqueous solution sodium thiosulfate, then with brine, and finally dried (Na2SO4) and evaporated. The crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 1.54 g (78%) of the title compound as yellow solids: MS (ESI) m/z 343 [M+H]+, 1H-NMR (CDCl3) δ 7.32 (4H, s), 3.86 (2H, t, J=6.6 Hz), 2.91 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.30 (3H, s), 1.67 (1H, br.s).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[NH:19][C:20](=[O:22])[CH3:21])C.[NH4+:24].[OH-]>>[C:20]([NH:19][C:7]1[CH:8]=[CH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:11][C:6]=1[CH2:5][C:4]([NH2:24])=[O:3])(=[O:22])[CH3:21]
Reactant: [NH4+]
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1NC(C)=O
Agent: [OH-]
Product: CC(=O)Nc1ccc(N2CCN(C)CC2)cc1CC(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[2-Acetylamino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetic acid ethyl ester (450 mg, 1.41 mmol) is suspended in a 33% aqueous NH4OH solution (200 mL), and stirred for 16 h at RT. The volume is carefully reduced under vacuum until the title compound remains as a brown solid, which is further dried under high vacuum. ES+-MS: 291 [M+H]+.
Reaction SMILES: [CH2:1](O)[CH3:2].[Br:4][C:5](=[CH:9][OH:10])[C:6](=[O:8])[CH3:7]>C1(C)C=CC=CC=1>[Br:4][C:5](=[CH:9][O:10][CH2:1][CH3:2])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)C(Br)=CO
Reactant: CCO
Solvent: Cc1ccccc1
Product: CCOC=C(Br)C(C)=O
Yield: 100 %

Procedure:
A mixture of 400 ml absolute ethanol and 60 ml toluene was heated to reflux and 20 ml of azeotrope was removed via a Dean Stark trap. To the ethanoltoluene solution was added 33.0 g (0.2 mole) of 3-bromo-4-hydroxy-3-buten-2-one and reflux was continued for 2 hours during which period three aliquots of 20 ml of ethanol-toluene were removed via the trap. The solution was concentrated in vacuo to give 38.6 g (100%) of 3-bromo-4-ethoxy-3-buten-2-one as a mobile oil. 1H-NMR(DMSO-d6)ppm(delta): 8.21 (s, 1H), 4.23 (q, 2H), 2.33 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [Si:1]([O:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]1[CH2:31][OH:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35](OC)=[O:36].O1CCCC1.[H-].[Na+]>O>[Si:1]([O:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]1[CH2:31][O:32][CH2:34][CH2:35][OH:36])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1COCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 48 (4.56 g), methyl bromoacetate (2.22 mL) and tetrahydrofuran (25 mL) were stirred at 0° C., 60% sodium hydride suspension (400 mg) was added into the solution. The reaction solution was stirred at room temperature for overnight, added water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→85:15). The obtained compound (1.46 g) was added tetrahydrofuran (20 mL), methanol (1 mL) and lithium borohydride (117 mg) and stirred at room temperature for 2 hours. The reaction solution was added water and aqueous 5% potassium sulfate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (1.40 g) having the following physical properties.
Reaction SMILES: [C:1]([O:4][C@@:5]1([C:28]#[CH:29])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14]([CH:15]=[C:16]([O:23]CC)[CH2:17][CH2:18]1)=[C:13]([CH:26]=O)[CH2:12]3)(=[O:3])[CH3:2].[BH4-].[Na+].S(=O)(=O)(O)O>C(O)C.CN(C=O)C>[C:1]([O:4][C@@:5]1([C:28]#[CH:29])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[C:13](=[CH2:26])[CH2:12]3)(=[O:3])[CH3:2]
Reactant: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC(C=O)=C4C=C(OCC)CC[C@@H]4[C@H]3CC[C@@]21C
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 84.4 %

Procedure:
2.8 g of 17beta-acetoxy 3-ethoxy 17alpha-ethynyl 6-formyl 3,5-estradiene, 8.5 ml (abs) ethanol (3.03 vol), 7 ml dimethylformamide (2.5 vol), and 0.13 g sodium borohydride (0.046 p) are introduced under agitation and under a nitrogen atmosphere into a 50 ml three-necked flask. The reaction is stopped after agitation for 22 hours. The reaction medium is hydrolyzed by introducing a solution composed of 2.8 ml (1 vol) of 2N sulphuric acid, 6 ml (2.1 vol) DMF, and 6 ml (2.1 vol) (abs) ethanol over 10 minutes. 2.1 g (yield=84%) of a creamy white product is obtained. M.p.=157° C.