Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:11]([CH2:13][CH:14]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH:15]1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)#[N:12].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:12][CH2:11][CH2:13][CH:14]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH:15]1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CC#N)C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CCN)C(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.67 h
Yield: 72.7 %

Procedure:
To a solution of aluminum chloride (190 mg) in THF (4.0 mL) was added lithium aluminum hydride (203 mg) under ice-cooling, and the mixture was stirred for 40 min. To this reaction solution was added dropwise a solution of tert-butyl (6RS,7RS)-7-(cyanomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (550 mg) obtained in Example 483, step A in THF (4.0 ml), and the mixture was stirred at 0° C. for 1 hr under an argon atmosphere. To the reaction solution was added aqueous sodium sulfate solution, and the mixture was stirred for 1 hr, and filtered through celite. The solvent of the filtrate was evaporated under reduced pressure to give the title compound (404 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1ccc(F)c(Cl)c1
Product: O=C(NCc1ccc(F)c(Cl)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (3-chloro-4-fluorophenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]=[CH2:14].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:2])[CH:13]=[CH2:14]
Reactant: C=CCOCCOCCOCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOCCOCCOCCO
Reaction time: 0.5 h

Procedure:
To a stirred solution of ester (14) (4.60 g, 21.1 mmol, 1.0 equiv.) in THF (60 mL) was carefully added one portion of LAH (0.50 g, 12.5 mmol, 0.5 equiv.) at 0° C. After 30 min, another portion of LAH was carefully added and the reaction was stirred for an additional 30 min. The reaction was then carefully quenched with a Na2SO4-saturated aqueous solution. The resulting white aluminum salts were then filtered off over a short plug of Celite (EtOAc washings) and the filtrate was finally evaporated under reduced pressure to afford pure alcohol (15) (no purification required) as a pale yellow oil (3.89 g, 97%). Spectroscopic data were consistent with those reported in the literature:26a 1H NMR (400 MHz, CDCl3) δ 5.93 (ddt, J=17.2, 10.3, 5.7 Hz, 1H), 5.28 (dq, J=17.2, 1.5 Hz, 1H), 5.19 (dq, J=10.3, 1.5 Hz, 1H), 4.04 (dt, J=5.7, 1.5 Hz, 2H), 3.78-3.58 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 134.8, 117.3, 72.7, 72.4, 70.8, 70.7, 70.5, 69.5, 61.8.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.BrN1C(=O)CC[C:20]1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1)[CH3:20]
Reactant: Cc1ccc2c(c1)CCc1ccccc1C2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 80 °C

Procedure:
60.5 Gm. of 2-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is refluxed in 500 ml. of carbon tetrachloride with 58.2 gm. of N-bromosuccinimide for 8 hours. The solution is cooled and filtered and the solvent removed under vacuum. The residue is dissolved in 200 ml. of dimethylformamide and 44 gm. of 1,5-diazabicyclo[3.4.0]nonene-5 is added. The mixture is heated to 80° C. for 20 minutes, then cooled and added to water. The solution is extracted with ether and the extract washed, dried and evaporated. The residue is recrystallized from acetone/hexane to afford 39.7 gm., 69%, of 2-methyl-5H-dibenzo[a,d]cyclohepten-5-one,m.p. 78°-80° C. Use of 2-ethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one gives a similar yield of 2-ethyl-5H-dibenzo[a,d]cyclohepten-5-one,m.p. 62°-64° C.
Reaction SMILES: C1(C)C=CC(S(NN=[C:12]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=O)=O)=CC=1.C([Li])CCC.CN([CH:30]=[O:31])C>CCN(CCN(CC)CC)CC.CCCCCC>[C:12]1([CH:30]=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)NN=C2CCCCCCCC2)cc1
Reactant: CN(C)C=O
Agent: CCN(CC)CCN(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=CC1=CCCCCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To cyclononanone p-toluenesulfonyl hydrazone (2.0 g) suspended in N,N,N′,N′-tetraethylenediamine (20 ml) was added dropwise at −55° C. a 1.6 M solution of n-butyllithium in hexane (16.2 ml). The resulting mixture was stirred at room temperature for 30 minutes under an argon atmosphere, was then cooled with ice, was mixed with DMF (2.5 ml) and was stirred at room temperature for one hour. The reaction mixture was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent. The residue was subjected to purification using a silica gel column (ethyl acetate:hexane=1:10) to obtain cyclononene-1-carbaldehyde (0.7 g) as a light yellow oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH2:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[N:7]=1)(=O)[CH3:2]>N1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:8]2[N:7]3[C:1]([CH3:2])=[N:4][N:5]=[C:6]3[CH2:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[CH:19]=1
Reactant: CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: c1ccncc1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A suspension of 3.3 parts of 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared in Example 25 in 20 parts by volume of pyridine is refluxed, whereby the crystals are gradually dissolved. After 2 hours the solvent is evaporated under reduced pressure. The residue is recrystallized from a mixture of acetone and n-hexane to yield 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as colorless needles melting at 224° C to 225° C.
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[C:26]([NH2:28])[N:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1)(C)(C)C.N>C(Cl)Cl>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[N:23]=[CH:24][N:25]=[C:26]([NH2:28])[CH:27]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(N)ncn2)cc1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(Cc2cc(N)ncn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 4 N solution of HCl in dioxane (19.2 mL, 76.4 mmol, 30 equiv) is added to a solution of [4-(6-amino-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (770 mg, 2.56 mmol) in CH2Cl2 (23 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 1.5 h and concentrated in vacuo. To the residue is added a 2 M methanolic solution of ammonia (3.8 mL, 7.68 mmol, 3 equiv) and the resulting yellow solution is concentrated in vacuo. The crude product is purified by silica gel (90 g) column chromatography CH2Cl2/MeOH, 90/10, then 80/20). The title compound is obtained as a white solid: ES-MS: 201.0 [M+H]+; single peak at tR=2.00 min (System 2); Rf=0.20 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:33]4[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(N4CCN(S(C)(=O)=O)CC4)ncc3O2)CC1
Temperature: 105 °C

Procedure:
4-(5-Chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg) is added to a mixture of 1-(methylsulfonyl)piperazine hydrochloride (70 mg), Pd2(dba)3 (65 mg), Xantphos (123 mg), and potassium tert-butylate (75 mg) in toluene (4 mL) under an argon atmosphere. The reaction mixture is stirred in an oil bath at 105° C. over night. After cooling to room temperature water is added and the mixture is extracted with ethyl acetate. The combined extracts are concentrated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) to give the title compound. LC (method 1): tR=1.03 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:46])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:42])([C:33]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:34])[CH3:32])[NH:17][CH:16]2[C:43]([OH:45])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:52][C@@H:51]([CH2:53][CH2:54][NH2:55])[CH2:50][O:49]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:52][C@H:51]([CH2:50][OH:49])[CH2:53][CH2:54][NH:55][C:43]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:46])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:42])([C:33]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])[CH3:32])[NH:17]1)=[O:45]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C(=O)Oc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C(=O)Oc1ccccc1
Yield: 54.1 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenoxycarbonyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 104c (0.75 g, 1.26 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.52 g, 3.6 mmol), HATU (0.82 g, 2.16 mmol) and iPr2NEt (1.04 mL, 6 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methyl-2-phenoxycarbonyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.45 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:9][C:8](=[O:18])[N:7]([CH2:19][CH3:20])[C:6]=2[CH:21]=1.Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:34][C:33]=2[O:44][CH3:45])[C:28]([Cl:46])=[CH:27][N:26]=1>>[Cl:46][C:28]1[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:34][C:33]=2[O:44][CH3:45])=[N:30][C:25]([NH:1][C:2]2[C:3]([O:22][CH3:23])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH2:9][C:8](=[O:18])[N:7]([CH2:19][CH3:20])[C:6]=3[CH:21]=2)=[N:26][CH:27]=1
Reactant: CCN1C(=O)CN(CC(=O)N(C)C)Cc2cc(OC)c(N)cc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CN(CC(=O)N(C)C)Cc2cc(OC)c(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc21

Procedure:
The title compound was prepared from 2-(8-Amino-1-ethyl-7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to example 724. Product was isolated as a tan solid (0.017 g, 18%). Mp 98-101° C.; LCMS (m/e) 639 (M); 1H-NMR (DMSO, 400 MHz) δ 8.10 (s, 1H), 8.08 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.54-7.52 (d, 1H, J=8.84 Hz, 6.99 (s, 1H), 6.61 (d, 1H), 6.37-6.34 (d, 1H, J=10.61 Hz), 3.86 (s, 3H), 3.80-3.74 (m, 8H), 3.53 (s, 3H), 3.12-3.11 (t, 4H, J=4.8 Hz), 3.02 (s, 3H), 2.97 (s, 2H), 2.83 (s, 4H), 1.19-1.18 (d, 1H, J=6.32 Hz), 0.90-0.86 (t, 3H, J=7.33 Hz).
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1.CN([CH:25]=[O:26])C>C1COCC1.CCOCC.O.CC(O)=O>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([CH:25]=[O:26])=[C:16]([F:21])[CH:15]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cc(Br)cc1F
Reaction time: 0.08 h
Yield: 66.7 %

Procedure:
n-BuLi (2.7M solution in heptane, 134 mL, 0.36 mol) was added drop wise at ˜75° C. to a solution of (i-Pr)2NH (51 ml, 0.36 mol) in THF (300 mL) and the mixture was stirred at the same temperature for 5 min. 1-Bromo-3,5-difluorobenzene (CAS 461-91-1) (70 g, 0.36 mol) in THF (100 ml) was added to the mixture at ˜80° C., and the mixture was stirred at the same temperature for 2 h. DMF (28 mL, 0.36 mol) was added to the mixture at ˜80° C., and the mixture was stirred at the same temperature for 15 min. A solution of AcOH in Et2O (1:1, 100 ml) was added to attain pH ˜4-5 at ˜80° C., and the reaction mixture was stirred at RT for 15 min. Water (500 mL) was added, and the layers were separated. The aqueous layer was extracted with Et2O (300 mL). The combined organic phases were washed with water, brine, dried with anhydrous Na2SO4 (100 g), evaporated and recrystallized from hexane to give the title compound (53.5 g, 67%, 0.24 mol) as white crystals. GC/MS data: 219 and 221 (M−H)+; 220 and 222 (M)+ (calculated for C7H3BrF2O 221). 1H NMR data (DMSO-d6): δ 10.15 (s, 1H, CHO), 7.71-7.65 (m, 2H, Ar—H).
Reaction SMILES: C([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][C:9]21[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(Cl)Cl>[C:11]1(=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]2([CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)[NH:10]1
Reactant: O=C1NC2(CCCCN2)C(Cc2ccccc2)c2ccccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C1NC2(CCCCN2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of intermediate compound IV (1.0 eq) and Protol Sponge (Aldrich, 1.0 eq) in CH2Cl2 under N2 was cooled to 10° C. A solution of 1-chloroethyl chloroformate (1.5 eq) in CH2Cl2 was added in a dropwise fashion over 30 min, and the reaction was stirred for 2 h while warming to room temperature. The reaction mixture was then subjected to chromatography by vacuum filtration (SiO2:CH2Cl2/Acetone). The resulting white solid was then suspended in MeOH and refluxed for 30 min. The solvent was then removed in vacuo to afford the desired product as the hydrochloride salt (70% yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:29])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:29])=[CH:24][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: O=C(c1ccc(O)cc1)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc4ccccc4c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with (4-Hydroxy-phenyl)-naphthalen-2-yl-methanone from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C30H28O6 [M+H]+: 485.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[CH2:26](O)[CH3:27].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:26][CH3:27])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reaction time: 3 h

Procedure:
52.4 g (0.15 mol) of 1-benzyl-3-(5-carboxy-2-furyl)indazole, potassium salt, were initially charged in 1250 ml of toluene, and after addition of 200 ml of abs. ethanol and 50 ml of conc. sulfuric acid the mixture was stirred under reflux on a water separator. After 3 hours, the mixture was concentrated using a rotary evaporator, the oil that remained was taken up in water/ethyl acetate and the aqueous phase was separated off. The organic phase was washed with water and 7.5% strength NaHCO3 solution, dried with sodium sulfate and concentrated. The residue was recrystallized from isopropanol. This gave 37.8 g (73%) of the title compound. m.p.: 98-99 ° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]1[C:26](=O)[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C([BH3-])#N.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][CH:21]2[CH2:22][CH2:23][C:24]3[C:19](=[CH:18][CH:17]=[CH:26][CH:25]=3)[CH2:20]2)=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCc2ccccc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(COc2ccc(NC3CCc4ccccc4C3)cc2)cc1
Yield: 92.5 %

Procedure:
A solution of 1.00 g (4.2 mmol, Aldrich) of 4-benzyloxyaniline hydrochloride, 560 μl (4.24 mmol, Aldrich) of β-tetralone and 132 mg (2.10 mmol) of sodium cyanoborohydride in 30 ml of MeOH over 3A molecular sieves was stirred at room temperature for 2.5 hours. The mixture was filtered, EtOAc was added and this was washed with saturated NaHCO3 twice. The organic layer was dried (MgSO4) and concentrated in vacuo. Purification via flash chromatography (silica gel, 1:10 EtOAc/petroleum ether) afforded 1.28 g (93%) of title compound as a golden yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Br)C.[F:20][C:21]([F:38])([F:37])[CH:22]1[CH2:24][N:23]1[S:25]([C:28]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=1[CH3:36])(=[O:27])=[O:26]>COC(C)(C)C.CCOCC.[Cu]I>[CH3:36][C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[C:33]([CH3:34])[C:28]=1[S:25]([NH:23][CH:22]([CH2:24][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][CH:10]=1)[C:21]([F:38])([F:20])[F:37])(=[O:26])=[O:27]
Reactant: c1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Agent: [Cu]I
Agent: CC[Mg]Br
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2c[nH]c3cccc(-c4ccccc4)c23)C(F)(F)F)c(C)c1
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a stirred solution of 115 mg (0.60 mmol) of 4-phenylindole in 2 mL of tert-butyl methyl ether at room temperature was added 0.25 mL (0.75 mmol) of a 3 M solution of ethyl magnesium bromide in ether. The mixture stirred for 30 minutes and then 22.8 mg (0.12 mmol) of copper (I) iodide was added. After 30 minutes, a solution of 87.9 mg (0.30 mmol) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine in 1 mL of tert-butyl methyl ether was added. After 18 hours, the reaction was quenched with 1 mL of ice-cold water. After 10 minutes, the reaction mixture was diluted with dichloromethane, filtered through CELITE® filter aid, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (12 g) eluting with ethyl acetate-hexanes (0-30% gradient) to afford an off-white solid. A second chromatography by preparative TLC eluting with ethyl acetate-hexanes (3:7) afforded 65 mg (22%) of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C.C(Cl)Cl.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([N:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:29][CH2:28]4)=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(CBr)N1CCc2ccccc21
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1CCc2ccccc21

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (10 g, 45.4 mmol), K2CO3 (7.2 g, 52.5. mmol) and N-(2-bromoacetyl)indoline (12 g, 50 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The mixture was cooled and filtered. The solution was concentrated down until solid appeared. The crystals were collected: weight 12.68 g. The mother liquor was concentrated to dryness. The residues were purified further by flash chromatography to yield an additional 1.35 g. Total yield was 14.03 g. A 2 g sample was dissolved in ethanol/methylene chloride and was treated with a solution of fumaric acid (612 mg) in ethanol to yield 2.58 g, m.p. 226°-227° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)#[N:27]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (24.9 mg, 67.7%), MS (ISP) m/z=460.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 4-cyanobenzoic acid.