Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:13]1[S:17][N:16]=[C:15](Cl)[N:14]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:13]1[S:17][N:16]=[C:15]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[N:14]=1)[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CN(CCCNC(=O)OC(C)(C)C)c1nc(Cl)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(CCCNC(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
{3-[(3-Chloro-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester (6.50 g, 21.2 mmol) was combined with imidazole (7.20 g, 105 mmol) and dissolved in DMSO (100 mL). Next, the sodium hydride (833 mg of a 60% dispersion on mineral oil, 57.8 mmol) was added the reaction mixture was stirred at 60° C. overnight. After this period, brine was added to the reaction mixture and it was transferred to a separatory funnel. The product was extracted with copious DCM and the organic layer was dried over anhydrous Na2SO4. The crude material was purified by flash silica chromatography (Hex to 1:4 Hex/EtOAc) to yield 6.78 g (94%) of {3-[(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester as a clear oil. [M+H]+ 339.10.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:11][CH:10]=1)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[O:7]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:11][CH:10]=1
Reactant: O=C(CCCCBr)Nc1ccc(COC(=O)CCCCBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCCCBr)OCc1ccc(N2CCCCC2=O)cc1

Procedure:
The ester from Step 1 (1 g, 2.22 mmol) was dissolved in DMF. Cs2CO3 (725 mg, 2.22 mmol) was added and the reaction mixture was heated to 50° for 18 hours. TLC shows ~50% starting material remaining. Additional Cs2CO3 (2.22 mmol) was added the reaction mixture was heated at 50° for and additional 8 hours. The mixture was dissolved in 10% citric acid and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried (MgSO4) filtered and concentrated to yield a yellow oil. Flash chromatography (EtOAc) yielded the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:18][CH:17]([CH2:19][OH:20])[CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:18][CH:17]([CH2:19][OH:20])[CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OCC1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Yield: 30.2 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.44 g, 20.0 mmol), azetidin-3-ylmethanol (2.25 g, 22.0 mmol) and DIPEA (5.21 mL, 30.0 mmol) in DMF (40 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between water and 2M aqueous K2CO3. The organic phase was washed with water and brine and dried over MgSO4. The crude product was purified by MPLC silica chromatography, eluting with 5% MeOH in DCM. Pure fractions were evaporated to dryness and triturated with ether, giving [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]azetidin-3-yl]methanol (1.65 g, 30%) as a cream crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)[CH:6]=[N:7][CH:8]=1)#[N:2].Cl.[NH2:17][C:18]([CH3:23])([CH3:22])[C:19]#[C:20][CH3:21]>>[C:1]([C:3]1[CH:4]=[C:5]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([NH:17][C:18]([CH3:23])([CH3:22])[C:19]#[C:20][CH3:21])=[O:13])[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: CCC(Oc1cncc(C#N)c1)C(=O)O
Reactant: CC#CC(C)(C)N
Agent: Cl
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C#N)c1

Procedure:
The product from Step 2 was condensed with 4-amino-4-methylpent-2-yne hydrochloride in a similar procedure to that described in Example 1 Stage 3 to give the required product as a colourless solid, m.p. 112–113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C=O.[C:22]([BH3-])#N.[Na+].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:22])=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: [BH3-]C#N
Reactant: Nc1ccc(NC(=O)[C@H]2CCCCN2)cc1[N+](=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 98.7 %

Procedure:
(R)—N-(4-Amino-3-nitrophenyl)piperidine-2-carboxamide (2.09 g, 7.9 mmol) was dissolved in MeOH (50 mL), and paraformaldehyde (0.95 g) and sodium cyanoborohydride (0.50 g, 8.0 mmol) were added. The mixture was stirred at room temperature for 70 min, and water added dropwise. The solvent was evaporated and the residue partitioned between water and EA (150 mL each). The phases were separated and the aqueous phase extracted with EA (2×100 mL). The combined EA layers were washed with brine, dried over magnesium sulfate, and concentrated to give (R)—N-(4-amino-3-nitrophenyl)-1-methylpiperidine-2-carboxamide as an orange foam (2.17 g), which was used without purification.
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Ca+2:5].[C:6](=[O:9])([OH:8])[O-:7].[Ca].[Mg:11].C(=O)(O)[O-].[Mg+2].C(=O)(O)[O-]>O>[C:1](=[O:2])([O-:4])[O-:3].[Ca+2:5].[C:6](=[O:7])([O-:9])[O-:8].[Mg+2:11]
Reactant: O=C([O-])O
Reactant: [Mg]
Agent: [Ca+2]
Agent: [Ca]
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])[O-]

Procedure:
Mixing lime with the water will result in the lime preferentially reacting with carbon dioxide and bicarbonates to cause calcium carbonate to precipitate as calcium carbonate particles. This ordinarily occurs at a pH of approximately 10 to approximately 10.3. Once the carbon dioxide demand has been met, the lime is free to react with calcium bicarbonate, for example, which further results in the precipitation of calcium carbonate particles. Calcium bicarbonate is typically the most common calcium compound found in untreated water but other calcium-based hardness compounds have similar reactions. Magnesium compounds have a slightly different reaction. Generally, magnesium bicarbonate reacts with lime and produces calcium carbonate and magnesium carbonate. Then the magnesium carbonate reacts with lime and creates more calcium carbonate and magnesium hydroxide. Both of these compounds precipitate out of water.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][NH:29][C:30]([CH:32]1[O:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]([C:42]([C:44]2[S:45][CH:46]=[C:47]([CH2:50][N:51]([S:53]([C:56]3[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=3)(=[O:55])=[O:54])[CH3:52])[C:48]=2[Cl:49])=[O:43])[CH2:33]1)=[O:31])(C(C)(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[Cl:49][C:48]1[C:47]([CH2:50][N:51]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH3:52])=[CH:46][S:45][C:44]=1[C:42]([N:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[O:37][CH:32]([C:30]([NH:29][CH2:28][CH2:27][OH:26])=[O:31])[CH2:33]1)=[O:43]
Reactant: CN(Cc1csc(C(=O)N2CC(C(=O)NCCO[Si](C)(C)C(C)(C)C)Oc3ccccc32)c1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(Cc1csc(C(=O)N2CC(C(=O)NCCO)Oc3ccccc32)c1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of tetrabutylammonium fluoride in THF (1.0M, 1.0 ml, 11.0 mmol) was added to a solution of N-(2-tert-butyldimethylsilyloxyethyl)-4-(3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorpholine-2-carboxamide (65 mg, 0.093 mmol) in THF (4.0 ml) and stirred for 1 h. The mixture was reduced, taken up in ethyl acetate, washed with 1N hydrochloric acid and brine, filtered and reduced. Chromatography (95% 60-80 petroleum ether/5% EtOAc) afforded 4-(3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carbonyl)-N-(2-hydroxyethyl)-benzomorpholine-2-carboxamide as a white solid (25 mg, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:26])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:26])[CH2:15][N:16]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Reactant: COC(=O)CNCc1ccc(OC)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(O)cc1

Procedure:
To a solution of 8.7 g (45.2 mmol) of 4-hydroxybenzenesulfonyl chloride in 80 ml of CH2Cl2, a solution of 6.75 g (32.3 mmol) of (4-methoxy-benzylamino)-acetic acid methyl ester in 20 ml of CH2Cl2 and 12 ml (79.2 mmol) of triethylamine were added dropwise at 0° C. The resulting mixture is stirred for 4 h at r.t., neutralized with cold 1N aqueous HCl and extracted with CH2Cl2. The combined extracts are washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:CH2Cl2=50:1˜5:1) to give [(4-hydroxy-benzenesulfonyl)-(4-methoxy-benzyl)-amino]-acetic acid methyl ester; NMR (CDCl3): 3.57 (s, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.40 (s, 2H), 5.59 (s, 1H), 6.84 (d, 2H, J=8.6 Hz), 6.93 (d, 2H, J=10.64 Hz), 7.15 (d, 2H, J=8.6 Hz), 7.82 (d, 2H, J=10.64 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH2:70][CH2:71][C:72]([O:74][CH3:75])=[O:73])=[CH:66][CH:65]=1>>[CH3:75][O:74][C:72](=[O:73])[CH2:71][CH2:70][C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 99.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (112 mg, 0.863 mmol), diphenylphosphinic chloride (106 mg, 0.446 mmol), then reacted with methyl 3-(4-aminophenyl)propanoate (31 mg, 0.173 mmol) to give rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-propionic acid methyl ester (108 mg, 56%). MS (ES+) m/z [(M+H)+]: 626
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-:26][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:26])[CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C=CC1(C)C
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of Celite™. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1-butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1 =H, R2-3 =methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL) was treated with 1.0 M BH3 -THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3 M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d, J=7.8, 1 H), 7.42 (t, J=7.8, 1 H), 7.31 (d, J=7.8, 1 H), 7.02 (t, J=7.8, 1 H), 2.73 (s, 2 H), 1.56 (s, 9 H), 1.49 (s, 6 H).
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:44]1[CH:49]=[N:48][CH:47]=[CH:46][N:45]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:49]=[N:48][CH:47]=[CH:46][N:45]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:5])[CH3:7])[CH2:14][CH2:13]1)=[O:17]
Reactant: Clc1cnccn1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cnccn2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (201 mg, 0.32 mmol) is coupled to 2-chloropyrazine (50 μL, 0.35 mmol) using Method B to give the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:16]1=2.N1C=CC=CC=1>ClCCl>[C:1]([N:14]([CH2:13][C:12]1[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:10]([C:9]([F:8])([F:40])[F:41])[CH:11]=1)[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:16]1=2)(=[O:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (5.47 g, 22.5 mmol) followed by titanium isopropoxide (5.98 mL, 20.1 mmol) to a solution of isopropyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (5.24 g, 16.1 mmol) in tetrahydrofuran (20 mL) at room temperature under nitrogen was and stir the solution for 4 h. Dilute the reaction with methanol (40 mL) and slowly add sodium borohydride (0.912 g, 24.1 mmol) over 15 min to the reaction and stir at room temperature for 3.5 h. Quench the reaction with addition of 2 N NaOH (56 mL) and water (50 mL) and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate/ethanol (4:1, 3×100 mL). Separate the filtrate and wash the organic layer with 2 N NaOH, 2 N HCl, and brine (50 mL each), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford isopropyl-5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (22.6 mL, 241 mmol) dropwise to a suspension of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (8.89 g, 16.1 mmol) and pyridine (19.6 mL g, 241 mmol) in dichloromethane (64 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (100 mL) and wash with 2 N hydrochloric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid (7.60 g, 79%, 2 steps): ESI MS 595 (M+H).
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].CS[C:7]1[N:12]([NH2:13])[C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1.CI>CO>[CH3:2][O:3][C:7]1[N:12]([NH2:13])[C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1
Reactant: CSc1nnc(-c2ccccc2)c(=O)n1N
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CI
Product: COc1nnc(-c2ccccc2)c(=O)n1N
Reaction time: 1 h

Procedure:
2.3 g sodium are added to 500 ml methanol whereby a sodium methylate solution is formed. 23.4g 3-methylthio-4-amino-6-phenyl-1,2,4-triazine-5-one (1a) and 6.5 ml methyl iodide are added. The mixture is boiled for 1 hour. When cooling down the mixture, a crystalline precipitate separates. The crystals are removed by suction and recrystallized from methanol and optionally once more from acetic acid ester. The 3-methoxy-4-amino-6-phenyl-1,2,4-triazin-5one (33") thus obtained has a melting point of 167° C.
Reaction SMILES: [Na].C[CH2:3][O:4][C:5](/[CH:7]=[C:8](/[CH2:10]P(OCC)(OCC)=O)\[CH3:9])=[O:6].[CH3:19][CH:20]([N:22]1[C:31]2[C:26](=[CH:27][C:28](/[C:32](/[CH3:36])=[CH:33]/[CH:34]=O)=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)[CH3:21].[Cl-].[NH4+]>CO>[CH3:21][CH:20]([N:22]1[C:31]2[C:26](=[CH:27][C:28](/[C:32](/[CH3:36])=[CH:33]/[CH:34]=[CH:10]/[C:8](/[CH3:9])=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)[CH3:19]
Reactant: C/C(=C\C=O)c1ccc2c(c1)CCCN2C(C)C
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: COC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)CCCN2C(C)C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
56 mg (2.46 mmol) of metallic sodium was added to methanol to prepare a meethanolic solution or sodium meethoxide. This solution was concentrated in a vacuum and suspended in N,N-dimethylformamide, followed by the addition of 560 mg (2.14 mmol) of triethyl 3-methyl-4-phosphonocrotonate under cooling with ice. After 30 minutes, 400 mg (1.64 mmol) of (E)-3-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-2-butenal was added to the mixture obtained above. The mixture thus obtained was stirred for one hour, followed by the addition of an aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (15% ethyl acetate/n-hexane) to give 330 mg of the title compound as a reddish-brown oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1.O>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH3:61])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:70])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol) in tetrahydrofuran (1 ml) was stirred at 60° C. for 2 hours. The solution was cooled to room temperature and then taken into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (82.4 mg, 99%).
Reaction SMILES: [CH2:1]([O:4][NH2:5])[CH2:2][CH3:3].C(Cl)CCl.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O>[CH2:1]([O:4][NH:5][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:2][CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CCCON
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Product: CCCONC(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
22 g (197 mmol) of n-propoxyamine hydroxhloride was dissolved in 100 ml of water, and 200 ml of ethylene dichloride was added thereto. Then, 27.2 g (197 mmol) of potassium carbonate was added in several times under cooling, and then 21.3 g (196 mmol) of ethyl chloroformate was dropwise added thereto at a temperature of not higher than 10° C. After raising the temperature to room temperature, the mixture was further stirred at the same temperature for 4 hours. The ethylene dichloride layer was separated, and then the aqueous layer was extracted twice with 100 ml of chloroform. The ethylene dichloride layer and the chloroform layer were put together, and washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. 27 g of ethyl N-n-propoxycarbamate was obtained by distillation under reduced pressure. Boiling point: 88° C./2.5 mmHg