Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.[CH3:24]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:9]=3[N:10]([CH3:24])[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Sodium hydride (60% weight dispersion in mineral oil, 4.19 g, 0.105 mol) was added portionwise to a solution of tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (23.6 g, 0.07 mol) in DMF (300 mL) at room temperature under N2. After 1 h, methyl iodide (14.8 g, 6.47 mL, 0.105 mol) was added, and the reaction was allowed to proceed for an additional 2 h. The mixture was quenched with H2O, upon which a solid precipitated out of solution. The suspension was therefore diluted to 2 L with H2O and filtered. The solids were washed thoroughly with water, then dissolved in CH2Cl2, dried over Na2SO4, filtered and concentrated to dryness. This provided the title compound (22.4 g, 91%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 4.60 (s, 2H), 3.81 (br t, 2H), 3.58 (s, 3H), 2.77 (t, J=5.4 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][OH:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:31][CH2:30][CH2:29][S:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: NCCSCCO
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCSCCO)ccc21
Yield: 77.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethylsulfanyl)-ethyl]-amide (70 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), 2-(2-amino-ethylsulfanyl)-ethanol (50 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1)/[CH:11]=[C:12]1/[C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH2:17]/1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:38]([C:42]1[CH:47]=[CH:46][C:45]([CH2:48]Cl)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]>C(OCC)(=O)C.O>[C:38]([C:42]1[CH:43]=[CH:44][C:45]([CH2:48][N:14]2[CH2:15][CH2:16][CH2:17]/[C:12](=[CH:11]\[C:10]3[CH:19]=[CH:20][C:21]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:8]([O:7][CH3:6])[CH:9]=3)/[C:13]2=[O:18])=[CH:46][CH:47]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: COc1cc(/C=C2\CCCNC2=O)ccc1-n1cnc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C2\CCCN(Cc3ccc(C(C)(C)C)cc3)C2=O)ccc1-n1cnc(C)c1
Reaction time: 0.5 h

Procedure:
To a DMF (2 mL) solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one (70 mg) obtained in Example 416, lithium bis(trimethylsilyl)amide (1M THF solution, 0.47 mL) was added dropwise under ice-cooling, and the reaction solution was agitated for 30 minutes under ice-cooling. Subsequently, 1-tert-butyl-4-chloromethylbenzene (0.073 mL) was added to the reaction solution, and the reaction solution was agitated for 30 minutes under ice-cooling. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system), and 37.8 mg of the title compound was obtained. The physical properties are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:37][CH2:36][S:35][CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCSCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCSCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 58 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.3 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-thiopyran-4-yl) piperazin-1-yl]benzonitrile (1.1 g), the title compound (1.1 g) was obtained, melting point: 281° C.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Br:40])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Br:40][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: CN(C[C@@H](N)c1ccc(F)c(Br)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(Br)c1

Procedure:
Compound 28 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a beige solid. LC/MS [419 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.40 (d, 1H), 9.02 (dd, 1.9 Hz, 1H), 8.60 (d, 1H), 8.40 (dd, 1H), 8.19 (s, 1H), 8.04-7.76 (m, 1H), 7.55 (ddd, 4.7, 2.1 Hz, 1H), 7.36 (td, 1H), 5.88-5.57 (m, 1H), 3.48 (t, 1H), 3.21 (dd, 1H), 2.54 (d, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Cc1ccc(N)cc1Cl
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C)c(Cl)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-chloro-4-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=1[O:52][CH3:53]>>[Br:44][C:45]1[C:46]([O:52][CH3:53])=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: COc1cc(O)ccc1Br
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Br)c(OC)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromo-3-methoxyphenol, the title compound was obtained (48%): 1H NMR (300 MHz, CDCl3) δ 9.85 (s, 1H), 7.52-7.38 (m, 2H), 7.22 (td, 1H), 6.94 (d, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 4.13-4.03 (br, 1H), 3.86 (s, 3H), 3.80-3.57 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 402 (M−17), 404 (M−17), 442 (M+23), 444 (M+23).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[C:12](=[O:20])[C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:22](=[O:29])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH2:23].[H-].[Li+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:25]([O:24][C:22]([NH:23][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[C:12](=[O:20])[C:8]3=[N:9]2)=[CH:4][CH:3]=1)=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1c2cc(F)ccc2-n2c1nc1cc(F)ccc1c2=O
Reactant: CC(C)(C)OC(N)=O
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=O)c1cc(F)ccc1-3

Procedure:
A solution of 3,8-difluoroindolo[2,1-b]quinazoline-6,12-dione (0.1 mmol, Example 36), t-butyl carbamate (0.11 mmol) and lithium hydride (0.12 mmol) in DMF (0.1 mM) is stirred at 70° C. for 12 h. The resulting reaction mixture is diluted with chloroform, washed with 0.1N HCl, sodium bicarbonate solution, dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (1% MeOH/CHCl3) gives 3-(N-t-butyloxycarbonylamino)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1([CH3:14])[CH:13]=[CH:12]C=[CH:10][CH:9]=1.[OH-].[Na+]>O>[CH3:14][C:8]1[CH:9]=[CH:10][C:2]([C:3]([OH:5])=[O:4])=[CH:12][CH:13]=1
Reactant: Cc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
A mixture of K2S2O8 (1.35 g), trifluoroacetic acid (4 mL), and the catalyst solution as prepared in Example 4(a) (1 mL) was stirred in air for 10 minutes. After toluene (5 mL) was added, the mixture was stirred under CO (1 atm) at room temperature for 66 hours. The mixture was diluted with water (5 mL), basified with NaOH, washed with ether, acidified with HCl, and thoroughly extracted with ether. The combined etherial extracts were evaporated to dryness. The residue was sublimed under vacuum to give 225 mg (TON=10) of p-toluic acid of >95% purity (1H NMR).
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@@H:8]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:21][CH2:20]1)[O:9][C@H:10]2[CH2:16][NH:17][CH3:18])(C)C.B(Cl)(Cl)[Cl:34]>ClCCl>[ClH:34].[ClH:34].[CH3:15][C:14]1[CH:13]=[CH:12][C:11]2[C@H:10]([CH2:16][NH:17][CH3:18])[O:9][C@H:8]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24]3)[CH2:7][C:6]=2[C:5]=1[OH:4]
Reactant: CNC[C@@H]1O[C@H](C2CCN(CCc3ccccc3)CC2)Cc2c1ccc(C)c2OC(C)C
Reactant: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC[C@@H]1O[C@H](C2CCN(CCc3ccccc3)CC2)Cc2c1ccc(C)c2O
Product: Cl
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Cool a solution of (1R,3S) [5-Isopropoxy-6-methyl-3-(1-phenethyl-piperidin-4-yl)-isochroman-1-ylmethyl]-methyl-amine in anhydrous dichloromethane (4 mL) to −20° C., and add 6 equivalents of BCl3 (using 1M BCl3 in dichloromethane) slowly into the solution. Following complete addition, stir the reaction mixture at −20° C. for 2 hours and 0° C. for 1 hour. Cool again to −20° C. and quench with anhydrous CH3OH (0.5 mL). Allow the resulting solution to warm to room temperature and concentrate. Purify the crude product on a 2 g SCX column and then by chromatography on a 1 g silica gel column (eluted by 7N NH3 in methanol:ethyl acetate=1:10). Collect and concentrate the appropriate fractions and treat with 2M HCl in diethyl ether to obtain the title compound. CIMS 395.4 (MH+), tR (min)=2.17.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16]C)=O)[CH2:3]1.F[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)[NH:32][C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)C1.F[C@H]1CN[C@H](C(NC2C=NC=CN=2)=O)C1>>[OH:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:32][C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C(Nc1cnccn1)[C@@H]1C[C@@H](F)CN1
Product: O=C(Nc1cnccn1)[C@@H]1C[C@H](O)CN1

Procedure:
(2S,4S)-4-Hydroxy-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide 85A was prepared from (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate as described for 65A and 65B. LC/MS [M+H]+: 209; Ret time (Method F): 0.27 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].[C:32](#N)[CH3:33].Cl[Si](C)(C)C.C(I)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[CH2:32][CH3:33])[C:8]([OH:10])=[O:9]
Reactant: CC#N
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Agent: C[Si](C)(C)Cl
Solvent: CCI
Solvent: O
Product: CCN1CCc2ccccc2[C@@]1(c1ccccc1)[C@H](Oc1cc(OC)cc(OC)c1)C(=O)O
Temperature: 55 °C
Yield: 27.2 %

Procedure:
To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (200 mg, 0.477 mmol, Example 1) in acetonitrile (5 ml) Hünig's base (327 μl, 1.91 mmol) followed by chlorotrimethylsilane (72 μl, 0.572 mmol) is added. The mixture is stirred at 55° C. for 3 h before ethyliodide (95 μl, 1.19 mmol) is added. Stirring at 55° C. is continued for another 16 h before water is added (about 200 μl). The solvent is removed under reduced pressure and the crude product is purified by prep. HPLC on Rp-C18 silica gel to furnish (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-2-ethyl-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (58 mg) as a white solid. LC-MS2: tR=4.20 min, [M+1]+=448.39, [M−1]−=446.34.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].F[C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C@H:24]2[CH2:26][O:25]2)=[C:17](C(=O)C)[CH:18]=1.[OH-].[Na+].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.Cl>ClCCl.N1C=CC=CC=1>[O:6]1[C:17]2[CH:18]=[CH:13][CH:14]=[CH:15][C:16]=2[O:22][CH2:23][C@@H:24]1[CH2:26][O:25][S:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1cc(F)ccc1OC[C@H]1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
3-Chloroperoxybenzoic acid (4.19 g, 17.00 mmol) was added in small portions to 1-[5-fluoro-2-((R)-1-oxiranylmethoxy)-phenyl]-ethanone (2.55 g, 12.13 mmol) in dichloromethane (13 ml) and the reaction mixture was refluxed for 24 hours. The cooled reaction mixture was washed twice with 10% NaHCO3 solution, once with aq NaOH solution and evaporated to dryness. 2M NaOH (10.9 ml, 21.84 mmol) was added to the evaporation residue and the mixture was heated to reflux for 1 hour. The cooled reaction mixture was extracted with dichloromethane and dichloromethane layer was evaporated to dryness. p-Toluenesulfonyl chloride (2.78 g, 14.56 mmol) was added in small portions to the evaporation residue in pyridine (7.5 ml) and the reaction mixture was stirred at RT. After 4 hours 1M HCl (7.5 ml) was added and the mixture was stirred for 1 hour at RT. The reaction mixture was extracted twice with ethyl acetate and the combined ethyl acetate layers were evaporated to dryness. The crude product was crystallized from 2-propanol to yield 2.58 g (63%) of the pure title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12]
Reactant: COC(=O)CCCCCCCCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCC=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
9-Hydroxy-nonanoic acid methyl ester (7 g) in dichloromethane was treated with pyridinium dichromate (35 g) and stirred at room temperature for 12 hours. The pyridinium dichromate was filtered, and the organic filtrate was washed by water. Hexane (3× volume) was added to the solution, and organic layer was collected and dried to obtain the crude product. The product was purified by Si gel column chromatography to yield ˜5 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[C:8]([Cl:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([CH:9]=[C:8]([Cl:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
To a solution of dimethyl 2,6-dichloroterephthalate (186 g, 707 mmol) in THF (600 mL) at room temperature was added a solution of sodium hydroxide (29.7 g, 742 mmol) in water (600 mL). The reaction mixture was stirred at room temperature for 48 hours and concentrated under reduce pressure to a volume of 600 mL. The residue was diluted with water (400 mL), cooled to 0° C. and acidified with 1 N HCl (800 mL). The resulting precipitate was collected by filtration and dried in vacuo to give 3,5-dichloro-4-(methoxycarbonyl)benzoic acid (72 g, yield: 41%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 3H), 7.92 (s, 2H). LCMS (ESI) m/z: 249.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]([F:7])([CH3:6])[C:3](=[O:5])[CH3:4].[Br-:8].[Br-:9].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:8][CH:4]([Br:9])[C:3](=[O:5])[C:2]([F:7])([CH3:6])[CH3:1]
Reactant: [Br-]
Reactant: CC(=O)C(C)(C)F
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(F)C(=O)C(Br)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a stirred solution of 3-methyl-3-fluoro-2-butanone (0.1031 g, 0.990 mmol) in anhydrous dichloromethane (5 ml) under nitrogen was added solid pyridinium tribromide (0.7035 g, 1.98 mmol) and the mixture was stirred at room temperature for 18 h. The mixture was then diluted with dichloromethane (5 ml), washed with dilute aqueous sodium hydrogensulfite (10 ml), then saturated aqueous NaCl (10 ml), dried (Na2SO4) and evaporated under low vacuum with no heat. The residue was purified by flash chromatography [silica gel, 5% Et2O/petroleum ether (40-60° C.)] to afford 0.1869 g (72%) of the title compound as a colourless oil: 1H NMR (360 MHz, CDCl3) δ 1.65 (6H, d, J 21.5 Hz), 6.51 (1H, d, J 1.5 Hz).
Reaction SMILES: [C:1]([C:3]1([CH2:10][CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:2][CH2:1][C:3]1([CH2:10][CH:11]2[O:12][CH2:13][CH2:14][O:15]2)[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2
Reactant: N#CC1(CC2OCCO2)CC2CCC1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1(CC2OCCO2)CC2CCC1C2
Yield: 84.6 %

Procedure:
8 g of 2-cyano-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.1]heptane are reduced with 4.4 g of lithium aluminum hydride in analogy to Example 1b. 6.9 g of a colorless oil are obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:15][CH2:14]1>CC1C=CC=CC=1>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1
Reactant: c1ccc2oc(NC3CCNCC3)nc2c1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Solvent: Cc1ccccc1
Product: O=C(NCCN1CCC(Nc2nc3ccccc3o2)CC1)c1ccc(F)cc1
Yield: 34 %

Procedure:
A mixture of 1.65 parts of 1-(4-fluorobenzoyl)aziridine (solution in benzene 1.2M), 2.1 parts of N-(4-piperidinyl)-2-benzoxazolamine and 90 parts of methylbenzene was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The product was filtered off and recrystallized from 2-propanone, yielding 1.3 parts (34%) of N-[2-[4-[(2-benzoxazolyl)amino]-1-piperidinyl]ethyl]-4-fluorobenzamide; mp. 173.3° C. (448).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]([F:14])([F:15])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(COC(F)(F)F)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(COC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 4-[(trifluoromethoxy)methyl]benzoic acid (500 mg, 2.27 mmol) in N,N-dimethylformamide (25 mL) were added iodomethane (300 μL, 4.82 mmol) and potassium carbonate (1000 mg, 7.24 mmol). The mixture was stirred at room temperature overnight, and then to the reaction solution was added water, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1→80:20) to give methyl 4-[(trifluoromethoxy)methyl]benzoate (453 mg, 85%) as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:16][CH2:17][CH2:18][OH:19])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(OC)O[CH2:22][CH:23]=[CH2:24].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CCOCC.CCCCCC>C1COCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:24]([O:19][CH2:18][CH2:17][CH2:16][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:23]=[CH2:22]
Reactant: CC(C)OC(=O)[C@H](CCCO)NC(=O)OC(C)(C)C
Reactant: C=CCOC(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)C
Temperature: 25 °C

Procedure:
A degassed mixture of isopropyl 2(S)-(tert-butoxycarbonylamino)-5-hydroxypentanoate (product of step 26C, 17.6 g, 63.9 mmol), allyl methyl carbonate (24.0 ml, 213 mmol), Pd2(dba)3 (1.62 g, 1.78 mmol) and BINAP (4.42 g, 7.10 mmol) in THF (150 mL) was refluxed under nitrogen for 3 hours. After cooling to room temperature, the reaction was diluted with ether, filtered through celite and evaporated giving a dark brown syrup. Flash chromatography of the residue (silica gel, 30% ether/hexane) gave isopropyl 5-allyloxy-2(S)-(tert-butoxycarbonylamino)pentanoate as a viscous colorless oil, 16.3 g (81%): 1H NMR (300 MHz, Chloroform-D) δ 5.88 (ddt, 1H, 17.4, 10.4, 5.5), 5.28 (m, 1H), 5.22-5.11 (m, 1H), 5.02 (sept., 1H, J=6.2Hz), 4.21 (br t, 1H, J=6.7Hz), 3.94 (dt, 2H, J=5.9, 1.5Hz), 3.42 (t, 2H, J=5.9Hz), 1.90-1.82 (m, 1H), 1.75-1.57 (m, 3H), 1.42 (s, 9H), 1.21 (d, 3H, J=6.2Hz), 1.19 (d, 3H, J=6.2Hz). LCMS m/z 316 (M+H)+.