Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[CH2:55][C:56]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[O:57]>O>[N:58]1([C:56](=[O:57])[CH2:55][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OCC(=O)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol) and cesium carbonate (63.4 mg, 195 μmol) were combined with dry dimethyl formamide (5 mL). 2-Chloro-1-morpholinoethanone (26.5 mg, 21.1 μL, 162 μmol) was added to the mixture with stirring. The tube was capped and heated at 50° C. After 1.5 h, the reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-morpholin-4-yl-2-oxo-ethyl ester as an off-white solid (104 mg, 86% yield) as product. LCMS (ES+) m/z calcd. for C37H39Cl2F2N4O6 [(M+H)+]: 743. found: 743.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)O)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([CH2:9][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C)c(C(O)c2ccc(C(F)(F)F)cc2)c1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1sc(C)c(Cc2ccc(C(F)(F)F)cc2)c1Br
Reaction time: 0.35 h

Procedure:
To a solution of (4-bromo-2,5-dimethyl-3-thienyl)[4-(trifluoromethyl)phenyl]methanol (74.0 g, 200 mmol) Example 11, Step 2 and triethylsilane (130 mL, 800 mmol) in 500 mL of dichloromethane at 0° C. under nitrogen is added trifluoroacetic acid (155 mL, 2.00 mol) such as to maintain an internal temperature between 1 and 4.5° C. Most of the volatiles are removed under reduced pressure and the resulting solution poured onto ether (1 L) and a mixture of sat. aq. sodium bicarbonate and water (500 mL). The phases are separated. The organic layer is washed with brine (200 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue is diluted and concentrated twice from toluene (300 mL). The residue is split in two equal parts, diluted with hexanes (each part with 30 mL) and each part is applied onto 330 g silica gel columns for purification with Combi Flash chromatography system (100% hexanes for 5 minutes then going to 5% ethyl acetate/95% hexanes over 21 minutes to afford the desired product as a colorless liquid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].P(Cl)(OC1C=CC=CC=1)([O:11][C:12]1C=CC=C[CH:13]=1)=O.C(N(CC)CC)C.C(O)(=O)C>C(OCC)(=O)C>[C:6]1(=[O:7])[N:2]([O:1][C:12](=[O:11])[CH3:13])[C:3](=[O:8])[CH2:4][CH2:5]1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C1CCC(=O)N1O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)ON1C(=O)CCC1=O
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
1.27 g (0.011 mol) of N-hydroxysuccinimide were initially introduced into 10 ml of ethyl acetate, a solution of 3.22 g (0.012 mol) of diphenyl chlorophosphate in 10 ml of ethyl acetate was added and then a solution of 2.53 g (0.025 mol) of triethylamine in 10 ml of ethyl acetate was added dropwise in the course of 10 minutes, the temperature rising to 41° C. A thick, white suspension resulted, which was treated with a solution of 0.6 g (0.01 mol) of acetic acid in 10 ml of ethyl acetate and heated at 45°-55° C. for 16 hours. After ending of the reaction, the solid was filtered off and washed with 2×3 ml of ethyl acetate. The combined filtrates were evaporated in vacuo and the semicrystalline residue which remained was washed by stirring with 20 ml of ethanol for 30 minutes. The white solid thus obtained was filtered off, washed with 2×3 ml of ethanol, sucked dry and then washed by stirring with 10 ml of isopropanol. After filtering off, washing with 2×2 ml of isopropanol and drying in vacuo, 1.1 g (70%) of white acetic acid succinimidyl ester were obtained.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(Br)cc12

Procedure:
In a manner similar to Example 17, 1-oxo-indan-4-carboxylic acid and 4-bromophenylhydrazine hydrochloride were reacted to form 8-bromo-5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acid which was converted to the ethyl ester in a manner similar to that described in Example 22 to afford the title compound as a tan solid: mp 198-200° C.; 1H NMR (DMSO-d6): δ 1.39 (t, 3H), 4.00 (s, 2H), 4.37 (q, 2H), 7.22 (d, 1H), 7.42 (d, 1H), 7.52 (t, 1H), 7.79-7.84 (m, 3H), 11.86 (s, 1H); MS [EI, m/z]: 355 [M]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[C:8]([O:12][C:13]([N:15]1[CH2:18][C:17](=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CC(O)=O.ClCCCl>[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)[CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: O=C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Reaction time: 16 h
Yield: 27.9 %

Procedure:
A mixture of piperazin-2-one (1.52 g, 15.1 mmol), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (2.0 g, 11.6 mmol) and trimethyl orthoformate (12.8 mL, 12.4 g, 117 mmol) in AcOH (0.7 mL) and DCE (50 mL) was stirred for 5 h before the addition of triacetoxyborohydride (4.9 g, 23.2 mmol). The resulting mixture was stirred for 16 h then partitioned between DCM and H2O. The organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as a foam (827 mg, 28%). 1H NMR (CDCl3, 300 MHz): δ 6.24 (s, 1 H); 3.97 (dd, J=8.9, 7.1 Hz, 2 H); 3.82 (dd, J=5.2, 2.2 Hz, 2 H); 3.40 (td, J=5.2, 2.2 Hz, 2 H); 3.24-3.15 (m, 1 H); 3.07 (s, 2 H); 2.60 (t, J=5.4 Hz, 2 H); 1.44 (s, 9 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:30][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:7][CH:8]=1)=[O:31]
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: C1CNCCN1
Product: O=C(Nc1ccc(OCCCN2CCNCC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and piperizine according to conditions described in general procedure L. A yellow powder is produced (0.194 g, 69%). Mp: 70-72° C. 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.23 (m, 1H), 7.86 (m, 1H), 7.55 (m, 2H), 7.45 (s, 1H), 7.42 (d, J=8.1Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.32 (m, 4H), 2.71 (t, J=4.5, 4H), 2.53 (m, 2H), 2.35 (brs, 4H), 2.02 (m, J=7.2 Hz, 2H), 1.60 (brs, 6H). MS: 491.2 (M+1).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1cccc(Cl)c1
Product: Clc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-chlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 336.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.58 (s, 1H); 8.45 (d, J=5.3 Hz, 1H); 8.01 (br s, 1H); 7.86 (m, 1H); 7.28 (m, 6H); 6.87 (d, J=5.3 Hz, 1H); 5.80 (br s, 1H); 4.74 (d, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:29]([O:31][CH3:32])=[O:30])=[O:4].Cl[C:34]1[CH:35]=[CH:36][C:37]2[O:50][CH2:49][N:40]3[C:41]4[CH:42]=[CH:43][CH:44]=[C:45]([F:48])[C:46]=4[CH:47]=[C:39]3[C:38]=2[N:51]=1>O1CCOCC1.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:48][C:45]1[C:46]2[CH:47]=[C:39]3[C:38]4[N:51]=[C:34]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([C:29]([O:31][CH3:32])=[O:30])=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[C:9]=6[CH:10]=5)[CH:35]=[CH:36][C:37]=4[O:50][CH2:49][N:40]3[C:41]=2[CH:42]=[CH:43][CH:44]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(C(=O)OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To a mixture of compound methyl 3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylate (700 mg, 1.50 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (536 mg, 1.95 mmol) and K3PO4.3H2O (1.20 g, 4.50 mmol) in 1,4-dioxane (25 mL), Pd2(dba)3/XPhos (50 mg/50 mg) was added under N2 protection. After stirring at 100° C. for 3 h, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:MeOH=200:1) to give the product of methyl 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carboxylate (700 mg, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 9.41 (br s, 1H), 8.79 (s, 1H), 7.74 (s, 1H), 7.55˜7.45 (m, 2H), 7.24˜7.17 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.88˜6.81 (m, 1H), 6.01 (s, 2H), 4.10 (s, 3H), 3.40 (s, 3H), 3.05 (d, J=4.4 Hz, 3H), 2.69 (s, 3H). MS (M+H)+: 579.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(OCC)(=O)C.CCCCCC>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 71 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-chlorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 71%. Melting point: 201-203° C. (Ethyl acetate-hexane)
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[CH:9]=[CH:10][C:11]=1[Cl:12]>CO>[Cl:19][C:18]1[C:13]([C:8]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([CH2:5][O:2][CH3:1])[CH:7]=2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
7.0 g of a 30% by weight solution of sodium methoxide in methanol were added to a solution of 5.0 g of 2-(3-bromomethyl-4-chlorophenyl)-3-chloro-5-trifluoromethylpyridine in 100 ml of anhydrous methanol. The mixture was refluxed for 8 hours and then concentrated. The residue was taken up in 100 ml of 10% strength hydrochloric acid, after which three extractions with 50 ml of ether each time were carried out. The ether phases were dried over sodium sulfate and concentrated. The oily residue was induced to crystallize with a little cold cyclohexane. Yield: 2.9 g (67%) of colorless crystals; melting point: 52°-54° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([CH:31](Br)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[C:25]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:4]2[CH2:5][CH2:6][NH:7][C:2]([CH3:1])([CH2:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[CH2:3]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(Cc2ccc3c(c2)OCCO3)CNCCN1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(Cc2ccc3c(c2)OCCO3)CN(C(c2ccccc2)c2ccccc2)CCN1
Yield: 91.8 %

Procedure:
12.4 g of 3-methyl-3-(3,4-ethylenedioxybenzyl)-piperazine (1a) are dissolved in 200 ml of dry acetone, combined with 20.7 g of potassium carbonate and 14.8 g of diphenylmethyl bromide, and heated for four hours with stirring under reflux. The inorganic salts are filtered off and the filtrate is evaporated to dryness is vacuum. The residue is taken up in 300 ml of diethyl ether and washed with water until the wash water no longer contains halogen. After drying with magnesium sulfate, hydrogen chloride is introduced into the organic phase. The precipitated hydrochloric is filtered off and washed with a little ether. Thereafter, it it suspended in a little water, combined with 20% ammonium hydroxide solution until alkaline, and extracted three times with 50 ml of diethyl ether. The organic phases are dried over magnesium sulfate and reduced to dryness. 19 g (91.6%) of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-piperazine (3a) are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH2:29][CH:30]=O)[CH:26]=[CH:27][CH:28]=1>>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[N:1]=[CH:30][C:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=1)=[C:12]2[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1cccc(C(F)(F)F)c1
Product: Oc1cccc(-c2c(-c3cccc(C(F)(F)F)c3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-Trifluoromethyl-phenyl)-acetaldehyde following the procedure of Example 457: HRMS: calcd for C23H13F6NO+H+, 434.09741; found (ESI, [M+H]+), 434.0993.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]([CH2:19][C@@H:20]([NH:27][CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][N:15]([CH3:14])[CH2:19][C@@H:20]([N:27]([CH3:28])[C:10](=[O:12])[CH2:9][C:8]([NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: CN[C@H](CN(C)CCO)c1ccccc1
Product: CN(CCO)C[C@H](c1ccccc1)N(C)C(=O)CC(=O)Nc1ccccc1

Procedure:
Coupling of the N-phenyl-malonamic acid (394 mg, 2.2 mmol) with 2-[methyl-(2-methylamino-(S)-2-phenyl-ethyl)-amino]-ethanol from step b above (562 mg, 2.0 mmol) using the general coupling method A yielded compound 21 (620 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ: 10.14, 10.11 (2s, total 1H), 7.60 (d, 2H), 7.31 (m, 7H), 7.05 (t, 1H), 5.82, 5.12 (m, total 1H), 4.41, 4.35 (2t, total 1H), 3.72–3.46 (m, 4H), 2.95–2.50 (m, 7H), 2.31, 2.26 (2s, total 3H); MS: [M+1]+: 370.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]2[N:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O1CCOCC1>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]3[N:22]=[N:23][NH:24][CH:25]=3)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Reactant: OB(O)c1cccc(Cl)c1
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: C1COCCO1
Solvent: O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Temperature: 90 °C
Yield: 19.9 %

Procedure:
(2S,4R)-5-(4-bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid (38 mg, 92 μmol) was combined with 3-chlorophenylboronic acid (28.9 mg, 185 μmol), sodium carbonate (29.4 mg, 277 μmol), water (0.2 mL) and dioxane (1.5 mL). The reaction vessel was sealed, air was removed by vacuum, and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18 μmol) was quickly added and air was removed by vacuum. The mixture was heated at 90° C. for 45 minutes. The mixture was acidified to pH ˜3 and filtered, and the solvate was concentrated. The residue was dissolved in AcOH (0.7 mL) and purified by preparative HPLC to yield the title compound (8.1 mg). MS m/z [M+H]+ calc'd for C22H23ClN4O4, 443.14. found 443.2.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])[CH2:9][CH2:8]1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C1COCC1>[C:18]([O:17][C:15]([N:13]([CH3:14])[C@H:10]1[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])[CH2:8][CH2:9]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)CCO[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCC(=O)O)CC1

Procedure:
15.3 g (48.5 mmol) of trans-3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyloxy]-propionic acid methyl ester in 485 mL of THF were treated with 485 mL of 1M LiOH at RT for 1 h. The solution was acidified by adding 1M KHSO4, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The crude product was triturated with n-heptane to give trans-3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyloxy]-propionic acid as white solid, MS: 300 (M−H)−.
Reaction SMILES: O=[C:2]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:11]1([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=2)[NH2:7])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1cccc(CC(=O)N2CCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 1.46 g of 3-(2-oxo-2-pyrrolidin-1-ylethyl)aniline obtained in stage b) below in 100 mL of tetrahydrofuran are added, under argon, 1.08 g of lithium aluminium hydride. The reaction mixture is stirred for one hour at room temperature and then cooled to 0° C. and treated successively with 1.08 mL of water, 1.08 mL of 15% (by weight) sodium hydroxide solution and 3.24 mL of water. The solid formed is filtered off and washed with ethyl acetate, and the filtrate is concentrated under reduced pressure to give 0.568 g of 3-(2-pyrrolidin-1-ylethyl)aniline, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)O)=[CH:5][CH:4]=1.[ClH:35]>CO>[ClH:35].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH2:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(C(O)c3ccc(OCCN4CCCC4)cc3)c3ccccc3CC2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: -20 °C

Procedure:
To a solution of the product of Example 14 (2.0 g, 4.58 mmol) stirring in methanol (50 mL) at ambient temperature was added methanolic hydrochloric acid (10 mL of a saturated solution). The reaction mixture was then concentrated to 20 mL and cooled to -20° C. for several hours. Filtration gave 0.62 g of the desired product as a white powder: 1 -NMR (CDCl3, 300 MHz) consistent with structure; MS (FD) m/e 437 (M+ -hydrochloric acid); Anal. Calc'd. for: C, 76.01; H, 6.80; N, 2.96. Found: C, 75.95; H, 6.76; N, 2.98.
Reaction SMILES: [B-](F)(F)(F)F.[CH:6]1[CH:12]=[CH:11][CH+:10][CH:9]=[CH:8][CH:7]=1.[C:13](=O)(O)[O-:14].[Na+]>CO>[CH3:13][O:14][CH:6]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: O=C([O-])O
Reactant: c1ccc[cH+]cc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Product: COC1C=CC=CC=C1

Procedure:
reacting an aqueous solution of cycloheptatrienyl tetrafluoroborate with methanol and sodium bicarbonate to produce 7-methoxycycloheptatriene;