Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C:10]([CH2:19][OH:20])([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:9][C@@:10]([CH2:19][OH:20])([CH2:17][O:18]2)[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@H:13]3[OH:14])=[CH:4][C:3]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(COc4ccccc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100.3 %

Procedure:
To a solution of (2S,3R,4S,5S)-2-(4-chloro-3-(phenoxymethyl)phenyl)-6,6-bis(hydroxymethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol (8.0 g, 18.16 mmol) in DCM (45 mL) under nitrogen atmosphere was added TFA (4.17 mL, 54.4 mmol) at 0° C. The reaction mixture was warmed to r.t. and stirred for 3-4 h. After the completion of the reaction as confirmed by TLC, the reaction mixture was quenched with saturated solution of sodium bicarbonate. The crude compound was extracted with DCM (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford crude title compound (7.45 g, 100%) as a white solid which was used without further purification for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][OH:16])=[CH:6][C:5]=1[CH3:17])([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][OH:16])=[CH:6][C:5]=1[CH3:17]
Reactant: Cc1cc(NCCNCCO)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1cc(NCCNCCO)ccc1N

Procedure:
The 2-[2-(4-nitro-3-methylphenylamino)ethylamino]ethanol (7) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[CH:4][CH:3]=1.[CH3:17][S:18]([CH2:21][C:22]1[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:24]=[CH:25][N:26]=1)(=[O:20])=[O:19].[H-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:23]4[CH:24]=[CH:25][N:26]=[C:22]4[CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:36][CH:35]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: ClCc1coc(/C=C/c2ccc(Br)cc2)n1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3)n2)cc1
Yield: 78.1 %

Procedure:
Using 2-[(E)-2-(4-bromophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (266 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (361 mg) as a colorless crystal powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15]2)=[O:13])=[N:8][CH:7]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>>[Cl:31][C:27]1[CH:26]=[C:25]2[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:9]3[S:10][C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([O:35][CH3:36])=[O:34])=[CH:7][N:8]=3)[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Reactant: COC(=O)Cl
Product: COC(=O)NCCCSc1cnc(NC(=O)N2CC3(CCN(C(=O)OC)C3)c3cc(Cl)ccc32)s1

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 3, with the exceptions that the methyl 1-((5-((3-aminopropyl)thio)thiazol-2-yl)carbamoyl)-5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate obtained in Step 1 of Example 454 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: [C:1](Cl)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O1CCCC1.[NH:16]=[C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[SH:19](=[O:27])([CH3:26])[NH:18]1.C(N(CC)CC)C>O>[C:1]([N:16]=[C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[SH:19](=[O:27])([CH3:26])[NH:18]1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(Cl)c1ccccc1O
Reactant: C[SH]1(=O)NC(=N)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[SH]1(=O)NC(=NC(=O)c2ccccc2O)c2ccccc21

Procedure:
A solution of 1.6 g. salicylic acid chloride in 5 cc. tetrahydrofuran is added dropwise, while stirring, to a solution of 1.8 g. 3-imino-1-methyl-3H-1,2-benzisothiazole-1-oxide and 1.2 g. triethylamine in 50 cc. tetrahydrofuran. The reaction mixture is stirred overnight at ambient temperature, thereafter poured into water and the precipitate obtained is filtered off with suction. There is thus obtained 3-(salicyloylimino)-1-methyl-3H-1,2-benzisothiazole-1-oxide which, after recrystallisation from ethanol, melts at 168° - 169°C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14]O)=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.O.[F-:41].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][F:41])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CC1)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCF)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.3 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(cyclopropylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (240 mg, 0.65 mmol) obtained in Example 351a) and triethylamine (140 μl, 1.00 mmol) in dichloromethane (10 ml) was added methanesulfonyl chloride (60 μl, 0.78 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (10 ml), tetrabutylammonium fluoride monohydrate (425 mg, 1.63 mmol) was added, and the mixture was stirred at 80° C. for 16 hr. After the reaction mixture was allowed to cool to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (90 mg, 37%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1[CH:10]=[CH:9][C:8]2C(=O)CC[CH2:14][C:7]1=2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:4]=[C:3]1[C:8]2[CH:9]=[CH:10][S:6][C:7]=2[CH2:14][CH2:1][CH2:2]1
Reactant: [Li]CCCC
Reactant: O=C1CCCc2sccc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCc2sccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes; 105.3 ml) was added dropwise under nitrogen at 0° C. over 30 minutes to a stirred solution of methyltriphenyl-phosphonium bromide (75.16 g) in tetrahydrofuran (250 ml), then the mixture was stirred at ambient temperature for 90 minutes. A solution of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (20 g) in tetrahydrofuran (200 ml) was added, the mixture was stirred at ambient temperature for 1 hour, then it was heated under reflux for 24 hours and cooled to ambient temperature. The solvents were removed in vacuo and the residue was purified by flash chromatography over silica using a 98:2 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 4-methylene-4,5,6,7-tetrahydrobenzo[b]thiophene (8.8 g) as a yellow oil which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:13]2[C:9]([S:10][C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=32)=[N:8][CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]3[C:6]([CH2:4][OH:3])=[CH:7][N:8]=[C:9]3[S:10][C:11]=2[CH:17]=1
Reactant: CCOC(=O)c1cnc2sc3cc(OC)ccc3n12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)sc1ncc(CO)n12
Yield: 83.6 %

Procedure:
A solution of 7-methoxy-imidazo[2,1-b]benzothiazole-3-carboxylic acid ethyl ester (5.5 g) in THF (150 mL) at 0° was treated with LiAlH4 (1.03 g) and reacted for 1 hour. The reaction was quenched by serial addition of water and 15% sodium hydroxide. The suspension was filtered, the combined filtrate and THF washes were evaporated to yield 7-Methoxy-imidazo [2,1-b]benzothiazole-3-methanol (Formula M-2) (3.9 g). Crystallization from acetonitrile solution gave 7-Methoxy-imidazo[2,1-b]benzothiazole-3-methanol (Formula M-2), m.p. 202-204°.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([O:8][C:9]([N:11]([CH3:51])[C@@H:12]([CH3:50])[C:13]([NH:15][C@H:16]1[C@H:22]([CH3:23])[O:21][C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[N:18]([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=O)=[CH:40][C:39]=3[C:47]#[N:48])[N:30]=2)[C:17]1=[O:49])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>[NH4+].[Cl-]>[C:47]([C:39]1[CH:40]=[C:41]([C:42](=[O:44])[NH:3][CH2:1][CH3:2])[CH:45]=[CH:46][C:38]=1[N:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([CH2:28][N:18]2[C:17](=[O:49])[C@@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([N:11]([CH3:51])[C:9](=[O:10])[O:8][C:4]([CH3:7])([CH3:5])[CH3:6])[CH3:50])[C@H:22]([CH3:23])[O:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]2=3)=[N:30]1)#[N:48]
Reactant: C[C@@H]1Oc2ccccc2N(Cc2nn(-c3ccc(C(=O)O)cc3C#N)c3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reactant: CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(-n2nc(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)Oc4ccccc43)c3ccccc32)c(C#N)c1
Yield: 91.5 %

Procedure:
Ethylamine (100 μl, 200 μmol, Eq: 3.11) was added to a mixture of 4-(3-(((2S,3S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-methyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-1H-indazol-1-yl)-3-cyanobenzoic acid (42 mg, 64.3 μmol, Eq: 1.00), DIEA (37.0 mg, 50 μl, 286 μmol, Eq: 4.45) and PyBOP (43.5 mg, 83.7 μmol, Eq: 1.3). After 16 h the mixture was diluted with sat. NH4Cl and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3, NH4Cl, and H2O, then dried over Na2SO4 and concentrated to give a residue that was purified by preparative TLC to afford tert-butyl (S)-1-((2S,3S)-5-((1-(2-cyano-4-(ethylcarbamoyl)phenyl)-1H-indazol-3-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (40 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([O:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[CH:21]=[N:20][CH:19]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(Cl)c1-c1ccc2[nH]cc(-c3cncc(O[C@@H]4CCCNC4)n3)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 3-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (0.077 g, 0.147 mmol) in 1.5 mL DCM was added TFA (0.170 mL, 2.208 mmol). After 30 min, the reaction was concentrated in vacuo, taken up in DMSO, and purified by RPHPLC, 10-100% ACN/H2O with 0.1% TFA; product-containing fractions were combined and concentrated in vacuo to give (R)-5-(2-chloro-6-fluorophenyl)-3-(6-(piperidin-3-yloxy)pyrazin-2-yl)-1H-indole bis(2,2,2-trifluoroacetate) as an orange solid. MS (ESI, pos. ion) m/z: 423 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[CH:24])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].S(=O)(=O)(O)[OH:31]>O.O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([CH3:24])=[O:31])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1=C(COCC(C)=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
A solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (1.06 g), mercuric sulphate (0.10 g) and concentrated sulphuric acid (0.2 ml) in a mixture of water (20 ml) and dioxane (20ml) was heated at 60° for 2 hours and then evaporated. The residue was partitioned between ether and water and the organic layer washed with saturated aqueous sodium chloride solution and water, dried over sodium sulphate and evaporated to give the title compund (0.93 g), m.p. 119°-121°. This material was confirmed spectroscopically to be idetnical to the product of preparation 6.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1.Cl>ClCCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7])[CH:18]=1
Reactant: COc1ccc(F)cc1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)/C=C/C(=O)c1cc(F)ccc1O
Temperature: 50 °C

Procedure:
Into 100 ml of 1,2-dichloroethane, maleic anhydride (11.3 g, 114 mmol) and anhydrous aluminum chloride (31.0 g, 228 mmol) were dissolved by heating at 50° C. for 15 minutes, and then p-fluoroanisole (12.6 g, 100 mmol) was added dropwise. The mixture was refluxed for an hour and then poured into 60 ml of concentrated hydrochloric acid with 400 g of cracked ice. Resulting crystals deposited out therein were obtained through a filtration, washed with water and dried in vacuo to give 16.0 g (80.0%) of the subject desired compound as yellow crystals.
Reaction SMILES: C1(C)C(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=CC=1.N12CCCN=C1CCCCC2.ClCCl.[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[O:36])[CH:32]=[N:33][CH:34]=1>O>[Br:28][C:29]1[CH:30]=[C:31]([C:35]2[O:36][CH:12]=[N:11][CH:10]=2)[CH:32]=[N:33][CH:34]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClCCl
Product: Brc1cncc(-c2cnco2)c1
Reaction time: 5 h
Yield: 79.3 %

Procedure:
Toluenesulfonylmethylisocyanide (126 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (122 mg) were added to a dichloromethane (4 ml) solution containing 5-bromo-3-pyridinecarboxaldehyde (100 mg) at room temperature, followed by stirring for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 5:2), and a white solid of 5-(5-bromopyridin-3-yl)oxazole (96 mg) was thus obtained.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.C1(C)C=CC=CC=1.CCO>O.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>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Cc2ccc(I)cc2)cc1
Reactant: OB(O)c1ccsc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To a mixture of 1-(4-iodobenzyl)-4-methoxybenzene (0.300 g, 0.925 mmol), 2N aqueous NaHCO3 solution (1.85 mL, 3.7 mmol), and 3-thiopheneboronic acid (0.237 g, 1.85 mmol) in a solution of toluene/EtOH (17.6/0.8 mL) at ambient temperature under an atmosphere of nitrogen was added tetrakis(triphenylphosphine)palladium(0) (0.107 g, 0.093 mmol). The mixture was refluxed for 18 h, cooled to ambient temperature, and diluted with H2O (30 mL). After extracting with EtOAc (3×25 mL) and filtering the EtOAc through a silica gel bed, the organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash column chromatography (70% hexane in dichloromethane) to afford the title product as a white solid (0.125 g, 48%): 1H NMR (400 MHz, CDCl3): δ 7.50 (d, 2H, J=8.4 Hz), 7.40 (t, 1H, J=2.0 Hz), 7.36 (d, 2H, J=2.4 Hz), 7.20 (d, 2H, J=8.4 Hz), 7.12 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 3.94 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[C@H:5]1[CH2:4][CH2:3]2.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>C(O)=O>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH:27][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[CH2:13][CH2:12]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CN(C)CCCN
Solvent: O=CO
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCCCN(C)C)CC[C@@H]12
Reaction time: 48 h

Procedure:
Formic acid (97-98%, 47.5 ml) is added dropwise to a cooled and stiffed mixture of estrone methyl ether (71.0 g) and 3-dimethylaminopropylamine (158 ml). The resulting mixture is heated in an oil bath (165°-175° C.) for 20 hours. The reaction is quenched in ice water (total volume 700 ml) and the resulting alkaline (pH--9) mixture is extracted twice with CH2Cl2. The combined extracts are washed with dilute aq. NAOH and with brine, dried (Na2SO4), filtered, and concentrated, Hexane (250 ml) is added to the residue and a white fluffy precipitate is filtered off, The solvent is removed, leaving a residual light brown oil which slowly crystallizes. A portion (20 g) of this material is chromatographed over silica gel (500 g) packed as a slurry in 7.5% of 10% NH4OH--CH3OH in CH2Cl2. The column is eluted (300 ml fractions) with the same solvent system. The desired material (about 14 g) is eluted in fractions 13-26 and pooled in CH2Cl2. As this solution stands at 20°-25°, crystals form. After two days, the crystals (4.803 g), mp 184°-192° C. with rapid heating, are collected by filtration. More crystals form in the filtrate and after 3 days these are collected. The compound can be recrystallized from methanol-acetone in the freezer, giving the second title compound as crystals, mp 184°-186° C. decomposition (dec) with bubbling.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CO.ClCCl>[CH2:9]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N[C@@H]1CCCC[C@H]1NCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
60.0 g (525.4 mmol) of (±)-trans-1,2-diaminocyclohexane is dissolved in 750 ml of absolute methanol and cooled to 0° C. At this temperature, the drop-by-drop addition of 10.5 g (99 mmol) of benzaldehyde, dissolved in 100 ml of absolute methanol, is carried out. After a reaction time of 2 hours at 0° C., the addition in portions of a total of 3.74 g (99 mmol) of sodium borohydride is carried out. After 12 hours at 25° C., the reaction solution is suctioned off on diatomaceous earth, and the solvent is drawn off in a vacuum. The remaining oily residue is taken up in 500 ml of dichloromethane and washed three times with 100 ml of water each. After the organic phase is dried on sodium sulfate, the solvent is drawn off in a vacuum. The oily residue that is thus obtained is chromatographed on silica gel (eluant: methanol/aqueous ammonia solution 20:1).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][C:13](=O)[C:10]3([CH2:12][CH2:11]3)[C:9]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[CH3:23][O:24][NH2:25]>CO.C(Cl)Cl>[CH3:23][O:24]/[N:25]=[C:13]1\[CH2:14][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9](=[O:16])[C:10]2\1[CH2:12][CH2:11]2
Reactant: O=C1CN(Cc2ccccc2)C(=O)C12CC2
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CO/N=C1\CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
5-(Phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione (Example 128) (2.8619 g, 13.29 mmol), sodium acetate (2.23 g, 26.59 mmol), and O-methylhydroxylamine hydrochloride (2.22 g, 26.59) was dissolved in 65 mL of MeOH. The mixture was stirred at room temperature overnight and then diluted with 300 mL of DCM. The mixture was washed with sat. aq. NaHCO3 (200 mL), and the organics were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide (7Z)-5-(phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione 7-(O-methyloxime) (3.0864 g, 95%). LCMS: (M+H)+: 245.1.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]=1[OH:36])[C:17](OC)=[O:18])=O)C1C=CC=CC=1>[C].[Pd].CO>[O:18]=[C:17]1[C@@H:16]([NH:21][C:22](=[O:37])[NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]=2[OH:36])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)Nc1cc(OC)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CO
Product: COc1cc(NC(=O)N[C@H]2CCCCNC2=O)c(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 42.8 %

Procedure:
10% Palladium-carbon (Pd-C) (150 mg) was added to 10 ml of a methanol solution containing 500 mg of 2-[3-((1S)-5-benzyloxycarbonylamino-1-methoxycarbonylpentyl)ureido]-4-methoxy-6-tert-butylphenol. The mixture was subjected to catalytic reduction at normal pressure for 2 hours. After removing the catalyst, the reaction mixture was condensed. Methanol was added to the precipitated crystals and the crystals were collected by filtration to give 145 mg of 2-[3-((3S)-2-oxo-perhydroazepin-3-yl)ureido]-4-methoxy-6-tert-butylphenol (yield: 43%, melting point: 178°-179° C.).