Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=O)[CH:6]=[CH:5][C:4]=2[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].COC1CCN(CC2C=C3C(=CC=2)C[C@@H](N)CC3)CC1.N1(CC2C=C3C(=CC=2)C[C@@H](N)CC3)CCCCCC1>C1COCC1.O>[N:14]1([CH2:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@@H:2]([NH2:1])[CH2:11][CH2:10]3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1
Agent: COC1CCN(Cc2ccc3c(c2)CC[C@H](N)C3)CC1
Agent: N[C@H]1CCc2cc(CN3CCCCCC3)ccc2C1
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CCc2cc(CN3CCCC3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ((S)-6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin-1-yl-methanone (0.49 g) in THF (5 ml) was added dropwise to a suspension of lithium aluminum hydride (0.60 g) in THF (10 ml). The mixture was stirred at RT for one hour. Water (0.6 ml) was cautiously added dropwise, followed by sodium hydroxide solution (16%; 2 ml) and water again (2 ml). The resulting precipitate was filtered off and the filtrate was concentrated. The residue was taken up in hydrochloric acid (1N) and the solution was washed with diethyl ether. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted three times with dichloromethane (DCM). The combined organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 230.36 (C15H22N2); MS (ESI): 231 (M+H+). In an analogous manner, (S)-6-(4-methoxypiperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-ylamine and (S)-6-azepan-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-2-ylamine were prepared.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][NH2:12])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:13][N:14]1[CH:19]=[C:18]([CH2:20]Cl)[C:17]([C:22](OC)=[O:23])=[C:16]([Cl:26])[C:15]1=[O:27]>CC#N>[Cl:26][C:16]1[C:15](=[O:27])[N:14]([CH3:13])[CH:19]=[C:18]2[CH2:20][N:12]([CH2:11][CH2:10][C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[C:22](=[O:23])[C:17]=12
Reactant: COC(=O)c1c(CCl)cn(C)c(=O)c1Cl
Reactant: NCCc1nc2ccccn2n1
Solvent: CC#N
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccn3n1)C2
Temperature: 100 °C
Yield: 52.5 %

Procedure:
TEA (3.01 ml, 21.59 mmol) was added rapidly to a solution of 2-([1,2,4]triazolo[1,5-a]pyridin-2-yl)ethanamine (1.167 g, 7.20 mmol) and 1-methyl-2-oxo-1,2-dihydro-3-chloro-4-methoxycarbonyl-5-chloromethyl-pyridine (1.8 g, 7.20 mmol, see compound (6) of Example b1)) in MeCN (15 ml). The reaction was heated in a microwave at about 100° C. for about 40 min. The reaction was cooled to r.t. and the mixture was filtered through a Büchner funnel. The residue solid was triturated with water (2×20 ml). The resulting solid was filtered off on a Büchner funnel to afford the title compound (1.3 g, 3.78 mmol, 52.5% yield).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:14]=1)(=O)=O.C(O)(=O)C.[Sn].Cl>O>[SH:2][C:5]1[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[C:8]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:14]=1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(S)cc2c1OCCO2
Temperature: 90 °C
Yield: 89.7 %

Procedure:
243 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid and 654 cm3 of acetic acid were introduced into a balloon flask provided with an agitator and a condenser. The mixture was heated to 90° C. and then cooled to 45° C. 389 g of tin and 1,744 cm3 of hydrocloric acid were then added. The mixture was heated to 55°-60° C., cooled and poured into water. The precipitate was dried off, washed and dried. 166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 191°-192° C.; yield: 90%).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O)#[N:32].C(OC(N=NC(OCC)=O)=O)C.C1(C)C=CC=CC=1>O1CCCC1>[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:11][CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][NH:3][CH2:8][CH2:7]1)#[N:32]
Reactant: N#Cc1ccccc1O
Reactant: O=CN1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccccc1OCCN1CCNCC1
Yield: 23.1 %

Procedure:
1-Formyl-4-(2-hydroxyethyl)piperazine (4.95 g) was dissolved in tetrahydrofuran (100 ml), then triphenyl phosphine (10.14 g) and 2-cyanophenol (3.57 g) were added thereto, and 40% azodicarboxylic acid diethyl ester/toluene solution (13.5 ml) was added dropwise thereto, and the title compound (1.60 g) was obtained in the same manner as in Example 47-1).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:15][N:14]([P:16](=[O:20])([O-:19])[O:17][CH3:18])[C:13]1=[O:21])=O)C1C=CC=CC=1.[K:22].[H][H]>C(O)C.[Pd]>[NH2:11][C@H:12]1[CH2:15][N:14]([P:16](=[O:19])([O-:20])[O:17][CH3:18])[C:13]1=[O:21].[K:22]
Reactant: [H][H]
Reactant: COP(=O)([O-])N1CC(NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: [K]
Solvent: CCO
Product: COP(=O)([O-])N1C[C@H](N)C1=O
Reaction time: 0.5 h

Procedure:
3-Benzyloxycarbonylamino-2-oxo-1-azetidinylphosphonic acid, methyl ester, potassium salt (250 mg; see example 4) in ethanol (7 ml) was added to a pre-hydrogenated suspension of 10% palladium on charcoal (125 mg) in ethanol (3 ml). The mixture was vigorously stirred under a hydrogen atmosphere for 0.5 hour, the atmosphere was exchanged for fresh hydrogen, and stirring was continued for an additional 0.5 hour. The catalyst was then replaced and the mixture was stirred for another 15 minutes under hydrogen, filtered through Celite on a Millipore filter and solvent was removed in vacuo giving (S)-3-amino-2-oxo-1-azetidinylphosphonic acid, methyl ester, potassium salt.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15](=O)[NH2:16])[CH:14]=1)(=[O:8])[CH3:7]>CN(C)C=O>[C:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1cncc(C(N)=O)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)c1cncc(C#N)c1
Yield: 48.5 %

Procedure:
Phosphorus oxychloride (2.75 g) was added to a solution of 3-acetyl-5-carbamoylpyridine (2.8 g) in N,N-dimethylformamide (30 ml) with cooling on an ice-water bath. The mixture was stirred with cooling for 1.5 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (150 ml) and the mixture was extracted with ethyl acetate (100 ml). The extract was dried with magnesium sulfate and then evaporated. The residue was chromatographed on a silica gel column eluting with chloroform to afford 3-acetyl-5-cyanopyridine (1.21 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C.[NH4+].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][N:7]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a solution of 5-bromo-7-azaindole (Aldrich, 2 g, 10.15 mmol) in DMF (40.6 ml) at 0° C. was added sodium hydride (0.690 g, 17.26 mmol). The reaction was aged for 10 min followed by addition of SEM-Cl (2.340 ml, 13.20 mmol). The reaction was allowed to warm to RT and stir for 4 h. The mixture was diluted with saturated NH4Cl (30 mL) and product extracted with ethyl acetate (30 mL). The organic extract was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (50 g, 0-50% ethyl acetate/hexanes) to give the compound 4-1a (3.2 gm) as a clear oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1>>[Cl:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[CH:4][CH:5]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1ccc(CBr)cn1
Product: Cc1cc(O)nc(SCc2ccc(Cl)nc2)n1
Yield: 62 %

Procedure:
The title compound was prepared by following the procedure described for Example 55 from 6-chloropyridine-3-carbaldehyde to provide (6-chloropyridin-3-yl)methanol, which was converted to 5-(bromomethyl)-2-chloropyridine. The reaction of 6-methyl-2-sulfanylpyrimidin-4-ol with 5-(bromomethyl)-2-chloropyridine provided 2-{[(6-chloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (0.82 g, 62% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 4.33 (s, 2H), 5.99 (bs, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 8.45 (s, 1H), 9.30 (s, 1H); M+268.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:7])[CH3:2].[CH3:19][S:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]CS([O-])(=O)=O)=[CH:26][CH:25]=1)(=[O:22])=[O:21]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][S:20]([CH3:19])(=[O:21])=[O:22])=[CH:29][CH:28]=2)=[CH:12][CH:13]=1)[CH3:7])[CH3:2]
Reactant: CS(=O)(=O)Oc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: CCOC(=O)C(OCC)C(C)c1ccc(O)cc1
Product: CCOC(=O)C(OCC)C(C)c1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1

Procedure:
3-(4-Hydroxyphenyl)-2-ethoxybutanoic acid ethyl ester was alkylated with 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate (described in Example 1a) using the same method as in Example 1(b) to give 2-ethoxy-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]-phenyl}butanoic acid ethyl ester as a diastereomeric mixture.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: C1(CS)C=CC=CC=1.BrCCCCCCCCO.C(SCCCCCCCCO)C1C=CC=CC=1.[C:36]1([CH2:42][S:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54])(=[O:45])=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(CS(CCCCCCCC(O)=O)(=O)=O)C=CC=CC=1.Cl.Cl.[CH2:77]([O:84][C:85](=[O:93])[CH2:86][C@@H:87]([NH2:92])[CH2:88][N:89]([CH3:91])[CH3:90])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([O:84][C:85](=[O:93])[CH2:86][C@@H:87]([NH:92][C:53](=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][S:43]([CH2:42][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:44])=[O:45])[CH2:88][N:89]([CH3:90])[CH3:91])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: O=S(=O)(CCCCCCCCO)Cc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCCCS(=O)(=O)Cc1ccccc1
Agent: OCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCS(=O)(=O)Cc1ccccc1

Procedure:
The title compound, m/e=427.4 ([M+H]+), was produced in analogy with example 59, steps 1 to 5. Thus, phenyl-methanethiol was alkylated in step 1 with 8-bromo-1-octanol, leading to 8-benzylsulfanyl-octan-1-ol, which was oxidized in step 2 to 8-phenylmethanesulfonyl-octan-1-ol. This was oxidized in step 3 to 8-phenylmethanesulfonyl-octanoic acid, then coupled in step 4 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(8-(phenylmethanesulfonyl)-octanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[NH3:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10]([NH2:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Reactant: N
Solvent: CCO
Product: NC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1

Procedure:
0.8 g (2.5 mmole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propanoate, 50 ml of aqueous ammonia and 10 ml of absolute ethanol was stirred at room temperature for 24 hours. The white precipitate obtained was collected by filtration. Recrystallization from isopropyl alcohol gave 0.45 g (56%), m.p. 213°-214° C. The formula C14H13BrN2O2 was verified through elemental analysis, C calculated 52.4, found 51.9. ##STR30##
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[N:29][N:28]=1>>[S:32]([C:30]1[S:31][C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:28][N:29]=1)(=[O:34])(=[O:33])[NH2:35]
Reactant: Nc1nnc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1nnc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 5-amino-[1,3,4]thiadiazole-2-sulfonic acid amide [commercially available, CAS 14949-00-9] according to general procedure II.
Reaction SMILES: [C:1](=[O:30])([O:5][CH2:6][O:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH:12]([P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])SCC.S(Cl)([Cl:34])(=O)=O>>[CH2:16]([O:15][P:13]([CH:12]([P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:11][CH2:10][CH2:9][C:8]([O:7][CH2:6][O:5][C:1]([Cl:34])=[O:30])=[O:29])([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOP(=O)(OCC)C(CCCC(=O)OCOC(=O)SCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CCCC(=O)OCOC(=O)Cl)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 47 neat (519.2 mg, 1.054 mmol) was cooled in an ice/water bath and sulfuryl chloride (128 μL, 1.579 mmol) was carefully added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. After removal of the excess sulfuryl chloride in vacuo, the crude acid chloride 48 was used directly in the next step without further purification. 1HNMR (400 MHz, CDCl3): δ 1.35 (t, J=7.0, 12H), 1.86-2.06 (m, 4H), 2.28 (tt, J=23.8, 6.2, 1H), 2.45 (t, J=7.0, 2H), 2.90 (q, J=7.3, 2H), 4.14-4.24 (m, 8H), 5.82 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:26]3[N:27]=[C:23]([CH2:22][F:21])[O:24][CH:25]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1coc(CF)n1
Product: C[C@@]1(c2cc(NC(=O)c3coc(CF)n3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 2-(fluoromethyl)oxazole-4-carboxylic acid [D. Banner et al. WO2011069934 (2011)] following General Procedure F yielded the title compound as a colorless solid. MS: m/z=419.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([NH2:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:23]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[C:27]=2[CH:26]=[CH:25][N:24]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([NH:15][S:33]([C:28]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:35])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)CNC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(CNC(=O)OCc1ccccc1)NS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 84.9 %

Procedure:
In 20 ml of a chloroform solution containing 2.23 g of 2-benzyloxycarbonylamino-1-methylethylamine and 1.2 g of triethylamine was added dropwise 20 ml of a chloroform solution containing 1.80 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and the reaction mixture solution was washed with water and dried with anhydrous magnesium sulfate. The chloroform was distilled therefrom under reduced pressure. The crystalline residue thus obtained was recrystallized from ethanol to give 2.68 g of N-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonamide in a yield of 85%.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:10]([C:14](Cl)(Cl)[Cl:15])([F:13])([F:12])[F:11].C(OC(=O)C)(=O)C>CN(C=O)C.O.[Zn]>[Cl:15][C:14]([C:10]([F:13])([F:12])[F:11])=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: Cc1ccc(C=O)cc1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C=C(Cl)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 390.7 %

Procedure:
12 g of p-tolualdehyde dissolved in 20 cc of DMF and 7.5 g of Zn are charged to a flask of 250 ml of capacity. 2.5 g of CF3CCl3 is dropwise added and the resulting reaction mixture is slightly heated until the reaction turns into strongly exothermic. Then 10 g of CF3CCl3 dissolved in 100 cc of DMF is dropwise added and the resulting mixture is stirred at room temperature for 4 hours. 10 cc of acetic anhydride and 13 g of Zn are then added. After 2 hours at room temperature, the reaction mixture is poured in acidic water and is extracted three times with ether; the ether phases are combined with one another, and are washed with a saturated solution of sodium bicarbonate, and with brine, and are then thoroughly dried and evaporated. The raw reaction product is chromatographed on silica (98/2 hexane/ethyl acetate). 11.5 g of 4-(2-chloro-3,3,3-trifluoroprop-1-enyl)-toluene is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[CH:26]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][CH2:24][N:8]3[C:7](=[O:25])[C:6]=2[C:26]=1[Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(N)ccc1-2
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(N)c1Br

Procedure:
1.5 g (4.2 mmol) of t-butyl (S)-7-amino-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 0.783 g (4.4 mmol) of N-bromosuccinimide in 15 ml of dimethylformamide are stirred at room temperature for 45 minutes, subsequently poured into 250 ml of water and extracted three times with chloroform. The chloroform solution is washed three times with water, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel using chloroform containing 4% methanol for the elution. Recrystallization of the material obtained from ethyl acetate yields t-butyl (S)-7-amino-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 245°-246°.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.Br[CH2:17][C:18](OCC)=[O:19]>CN(C=O)C.CCOC(C)=O.O>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH2:17][C:18]1=[O:19]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CNc2ccccc2N1
Temperature: 120 °C

Procedure:
To a solution of benzene-1,2-diamine (150 g, 1387 mmol) and triethylamine (193 mL, 1387 mmol) in DMF (Ratio: 20 times, Volume: 3000 mL) was added ethyl bromoacetate (232 g, 1387 mmol). The reaction mixture was heated at 120° C. for 36 h. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated to give crude material. The crude product was purified via ISCO, eluted with 50% EtOAC/hexane to afford 3,4-dihydroquinoxalin-2(1H)-one, Intermediate E-1A (140 g, 945 mmol, 68.1%). 1H NMR (400 MHz, CDCl3) δ ppm 7.7 (1H, bs), 6.9 (1H, m), 6.75 (1H, m), 6.70 (2H, m), 4.0 (1H, s), 3.85 (1H, bs).
Reaction SMILES: C(C1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(CC)=CN=1)C.[CH2:22]([C@H:24]1[C@H:32]([NH2:33])[C:28]2[CH:29]=[CH:30][S:31][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Br[C:35]1[C:40]([CH2:41][CH3:42])=[N:39][C:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])=[C:37]([CH2:51][CH3:52])[N:36]=1>>[Cl:50][C:44]1[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:43]=1[C:38]1[N:39]=[C:40]([CH2:41][CH3:42])[C:35]([NH:33][C@@H:32]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH2:26][CH2:25][C@H:24]2[CH2:22][CH3:23])=[N:36][C:37]=1[CH2:51][CH3:52]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Reactant: CC[C@@H]1CCc2sccc2[C@H]1N
Agent: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-5-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.35–7.28, 7.11, 6.91, 5.27, 4.58, 2.85, 2.64, 2.49, 2.08, 1.93, 1.84, 1.66, 1.41, 1.26, 1.18, 1.06; HRMS (FAB) calcd for C24H27Cl2N3S+H 460.1381, found 460.1398. Anal. Calcd for C24H27Cl2N3S: C, 62.60; H, 5.91; N, 9.13. Found: C, 62.36; H, 5.94; N, 8.91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[N:15]([CH3:16])[CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CN1C2CCC1CC(O)(c1ccc(Cl)cc1)C2
Solvent: O=C(O)C(F)(F)F
Product: CN1C2C=C(c3ccc(Cl)cc3)CC1CC2

Procedure:
Racemic 3-(4-Chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol (6.37 g, 25.30 mmol) was dissolved in trifluoroacetic acid (30.8 mL) and heated at reflux for 1 hour. The reaction was concentrated diluted with water (200 mL), adjusted to pH 10 with ammonium hydroxide, and extracted with diethyl ether (2×200 mL). The combined organic layers were washed with brine (100 mL), dried with magnesium sulfate and concentrated to yield racemic 3-(4-Chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene as a white solid which had the following properties: Mp. 82-84° C., 1H NMR CDCl3 δ: 7.27 (q, J=7.7 & 8.5 Hz, 4H), 6.24 (d, J=5.6 Hz, 1H), 3.45-3.36 (m, 2H), 2.82 (dd, J=4.2 & 12.7 Hz, 1H), 2.37 (s, 3H), 2.23-2.14 (m, 1H), 2.13-2.03 (m, 1H), 1.98 (d, J=17.2 Hz, 1H), 1.91-1.83 (m, 1H), 1.62-1.53 (m, 1H). IR (KBr): 3096, 3079, 3049, 3023, 2945, 2904, 2847, 2798, 2764, 2708, 2596, 2315, 2212, 1942, 1910, 1747, 1667, 1587, 1562, 1532, 1496, 1470, 1443, 1429, 1419, 1406, 1356, 1318, 1302, 1276, 1259, 1244, 1213, 1198, 1164, 1146, 1130, 1109, 1093, 1074, 1059, 1009, 992, 969, 942, 918, 873, 852, 834, 813, 799, 777, 746, 728, 706, 675, 632, 575, 546, 532, 469, 443, 414, (cm−1). Analysis calculated for C14H16ClN: C, 71.94; H, 6.90; N, 5.99. Found: C, 71.88, H, 7.20, N, 6.00.