Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]([OH:28])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:6]=2[CH:40]=1
Reactant: Cc1ccccc1CC(=O)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1CC(O)c1ccc(C(=O)N2CCCC(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cc1
Reaction time: 2 h
Yield: 100.6 %

Procedure:
7-Chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methylphenyl)acetyl]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.06 g) is dissolved in a mixture of methylene chloride (20 ml) and methanol (20 ml), and thereto ia added with stirring sodium borohydride (0.28 g) under cooling over an ice-bath. The mixture is stirred for two hours over an ice-bath, and the mixture is evaporated to remove almost of the solvent. To the residue is added water, and the mixture is extracted with methylene chloride. The organic layer is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol =20~10:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{4-[2-(2-methyl-phenyl)-1-hydroxyethyl]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.08 g) as colorless amorphous.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([NH:9][C:10]([C:12]1[CH:31]=[CH:30][C:15]2[N:16]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:17]([CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])#[N:2].[F:32][C:33]([F:39])([F:38])[C:34]([NH:36][NH2:37])=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:8][CH:6]([CH3:7])[CH2:5][C@H:4]([NH:9][C:10]([C:12]1[CH:31]=[CH:30][C:15]2[N:16]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:17]([CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11])[CH2:3][C:1]1[N:2]=[C:34]([C:33]([F:39])([F:38])[F:32])[NH:36][N:37]=1
Reactant: NNC(=O)C(F)(F)F
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@H](CC#N)CC(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@H](Cc3n[nH]c(C(F)(F)F)n3)CC(C)C)ccc21
Temperature: 200 °C
Yield: 9.6 %

Procedure:
A mixture of 50 mg 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyanomethyl-3-methyl-butyl)-amide, 45 mg of trifluoroacetic acid hydrazide and 4 mg of potassium carbonate in 0.6 ml of ethanol was heated to 200° C. in a microwave reactor for 24 h. The solvent was removed and the residue was purified by HPLC to obtain 6 mg (10%) of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid [(S)-3-methyl-1-(5-trifluoromethyl-1H-[1,2,4]triazol-3-ylmethyl)-butyl]-amide.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=1)=[C:24]=[O:25]>>[F:34][C:33]([F:35])([F:36])[O:32][C:28]1[CH:27]=[C:26]([NH:23][C:24]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:25])[CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1cccc(OC(F)(F)F)c1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1cccc(OC(F)(F)F)c1
Yield: 70 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 1-isocyanato-3-trifluoromethoxy-benzene (intermediate 15) gave the titled compound in 70% yield as white amorphous solid. MS: 513.23 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH:22]([CH3:24])[CH3:23])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])[OH:4].C(Cl)(Cl)Cl.[CH:36](=O)[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]>C1C=CC=CC=1>[CH:36](=[N:1][C@H:2]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH:22]([CH3:23])[CH3:24])[OH:4])[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]
Reactant: CC(C)Oc1ccccc1C(O)(c1ccccc1OC(C)C)[C@H](N)Cc1ccccc1
Reactant: O=Cc1ccccc1O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccccc1C(O)(c1ccccc1OC(C)C)[C@@H](Cc1ccccc1)N=Cc1ccccc1O

Procedure:
A mixture of 2.5 g. (5.9 millimols) of (R)-2-amino-1,1-di(2-isopropoxyphenyl)-3-phenyl-1-propanol {[α]D +65.0° (c 1.0, chloroform)} and 0.66 g. (5.4 millimols) of salicylaldehyde in 50 ml benzene was heated under reflux for 2.5 hours. After the distillation of the solvent from the reaction mixture, the residue was recrystallized from ethanol to give (R)-N-salicylidene-2-amino-1,1-di(2-isopropoxyphenyl)-3-phenyl-1-propanol as yellow crystals. Yield, 2.43 g. (85%); melting point, 152° - 153° C.; [α]D, +65.25° (c 1.00, chloroform).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(OCC)(=O)C.C(#N)C>[CH2:22]([NH:29][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccccc4)cc3)noc2c1
Yield: 55.1 %

Procedure:
Mix 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (150 mg, 0.43 mmol), benzylamine (92.2 mg, 0.861 mmol), potassium carbonate(130.6 mg, 0.95 mmol, 2.2 equivalents), potassium iodide (7.2 mg, 0.043 mmol) and 4%-5% aqueous acetonitrile (4-6 mL). Under a nitrogen atmosphere, heat (70°-75° C.) overnight. Dilute reaction mixture with ethyl acetate, filter to remove the solids and concentrate (in vacuo). Purify the crude reaction mixture by column (silica) chromatography using a Waters Sep-Pak 10 g cartridge eluted with ethyl acetate to give the title compound as a solid (89.23 mg, 55.1% Yield). Purity by LC/MS=95%, [M+H]+=377.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:26])[C:13]([NH:15][N:16]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]1[C:22]([O:24]C)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29][CH:28]=1>>[Br:21][C:18]1[CH:19]=[CH:20][N:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])[C:17]=1[C:22](=[O:24])[NH:33][C:31]1[CH:32]=[N:27][CH:28]=[N:29][CH:30]=1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: Nc1cncnc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cncnc1
Yield: 62.3 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(benzyloxycarbonylamino)propanamido)-3-bromo-1H-pyrrole-2-carboxylate (0.81 g, 1.91 mmol) and pyrimidin-5-amine (1.45 g, 15.3 mmol) following the experimental procedure described in Preparation 44a. 0.58 g (62% yield) of the desired compound were obtained.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].O.[NH2:16][NH2:17]>CO>[NH2:5][C@@H:4]([C:3]([NH:16][NH2:17])=[O:2])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: NN
Reactant: COC(=O)[C@H](N)Cc1ccc(O)cc1
Solvent: O
Solvent: CO
Product: NNC(=O)[C@H](N)Cc1ccc(O)cc1
Yield: 93.3 %

Procedure:
D-Tyrosine methyl ester (30 g, 129 mmol, 99% ee) was dissolved in 150 mL of methanol and stirred until dissolved. Hydrazine hydrate (23 ml, 453 mmol) was then added and solution stirred overnight. Methanol was removed at reduced pressure and saturated NaHCO3 was added (150 ml). The product was precipitated, filtered and dried to yield the title compound as a white powder (23.5 g, 93%). 1H NMR (CD3OD, 400 MHz) δ 7.03 (ad, J=8.8 Hz, 2H), 6.72 (ad, J=8.8 Hz, 2H), 3.44 (t, J=6.8 Hz, 1H), 2.91-2.86 (m, 1H), 2.76-2.71 (m, 1H). ESI-MS (m/z): 196.1 [M+1]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([Cl:17])[CH:13]=[CH:12][N:11]=1
Reactant: Fc1cccnc1Cl
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1c(Cl)ccnc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of lithium diisopropylamide (2 M in heptane/THF/ethylbenzene, stabilised with 0.5% w/w LiBr; 3.8 ml, 7.6 mmol) and THF (3 ml) was cooled to −78° C. and a solution of 2-chloro-3-fluoropyridine (1.0 g, 7.6 mmol) in THF (2 ml) was added dropwise over 1 min. After 2 h, a solution of hexachloroethane (2.0 g, 8.4 mmol) in THF (3 ml) was added dropwise and stirring continued for 2 h before quenching with saturated aqueous NH4Cl solution (20 ml) and extraction of the reaction product with EtOAc (100 ml). The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by column chromatography (silica; 15% Et2O/isohexane) to afford 2,4-dichloro-3-fluoropyridine (795 mg, 63%): δH (400 MHz, CDCl3) 7.34 (1H, t, J 5.1), 8.13 (1H, d, J 5.1); m/z (ES+) 166 (100%, [MH]+).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[SH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH3:22][C:16]([S:13][C:9]1[N:10]=[N:11][S:12][C:8]=1[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1nnsc1Cc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1nnsc1Cc1ccccc1

Procedure:
A solution of 1.99 g of 5-(phenylmethyl)-1,2,3-thiadiazole-4-thiol, sodium salt in 30 ml of ethanol was stirred overnight with 1.96 g of ethyl 2-bromoisobutyrate and then concentrated in vacuo. The residue was taken up in ether, filtered, and evaporated in vacuo. The oily residue was purified as described in Example 50, giving a yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90 MHz: 1.22 (t, 3H); 1.67 (s, 2 CH3 's); 4.12 (q, 2H); 4.31 (s, CH2); 7.30 (6s, SH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC3C=CC=CC=3)=[O:15])=[C:10]([CH3:24])[N:9]2[CH3:25])=[CH:4][CH:3]=1>CO.[H][H].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[C:10]([CH3:24])[N:9]2[CH3:25])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccc(F)cc2)n1C
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of benzyl 2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.6 g, 7.64 mmol) in methanol (25 mL), Pd/C (0.5 g) was added. While blowing in hydrogen gas, the mixture was stirred for 8 hours. The resulting reaction mixture was filtered by passing through a celite pad. The filtrate was concentrated under reduced pressure. The target compound was yielded (1.8 g, 94% yield).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:46]([C:49]1[S:53][CH:52]=[C:51]([C:54](O)=[O:55])[CH:50]=1)([CH3:48])[CH3:47].C(N(CC)CC)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:33]1[CH2:32][CH2:31][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:54]([C:51]3[CH:50]=[C:49]([CH:46]([CH3:48])[CH3:47])[S:53][CH:52]=3)=[O:55])[CH2:29]2)[CH2:35][CH2:34]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1
Reactant: CC(C)c1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.55 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)ethanol (example 82, step a) (0.32 g), 5-isopropylthiophene-3-carboxylic acid (0.19 g) and triethylamine (0.61 mL) in DMF (7 mL) at 0° C. The resulting yellow solution was allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.4 g.
Reaction SMILES: [C:1]([N:5]([C:7]1[O:8][C:9]2[C:10](=[C:12]([C:24]#[N:25])[C:13]([CH3:23])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]=2F)[N:11]=1)[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[C:1]([N:5]([C:7]1[O:8][C:9]2[C:10](=[C:12]([C:24]#[N:25])[C:13]([CH3:23])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]=2[N:37]2[CH2:38][CH2:39][C@H:35]([N:34]([CH3:40])[CH3:33])[CH2:36]2)[N:11]=1)[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C(C)(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)C(C)(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h

Procedure:
2-(N-tert-butyl-N-methylamino)-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-137) (0.22 g, 0.65 mmol) was suspended in dimethyl sulfoxide (5 ml), then triethylamine (0.19 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.17 ml, 1.34 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[S:35][C:36]([CH:39]=[O:40])=[CH:37][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[S:35][C:36]([CH:39]=[O:40])=[CH:37][N:38]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: O=Cc1cnc(Br)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ncc(C=O)s4)cc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (500 mg, 1.1 mmol) in dioxane (12 mL) and H2O (4 mL) was added 2-bromo-1,3-thiazole-5-carbaldehyde (634 mg, 3.3 mmol), potassium carbonate (898 mg, 8.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.181 mmol). Reaction was run in the microwave at 150° C. for 20 min. Aqueous work-up performed to give crude product. The reaction was then repeated in the microwave at 150° C. for 30 min to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-1,3-thiazol-2-yl)-1H-indole-7-carboxamide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:8]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1cccc(Cc2ccco2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Cc2ccco2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(furan-2-ylmethyl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-2-ylmethyl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 54%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:25])[CH2:11][C:12](=[O:24])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[CH:4][C:3]=1[O:26][CH3:27]>[Pd].C(OCC)(=O)C>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:12](=[O:24])[CH2:11][C:10](=[O:25])[CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:26][CH3:27])[CH:4]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(C=CC(=O)CC(=O)C=Cc2ccc(O)c(OC)c2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)CC(=O)CCc2ccc(O)c(OC)c2)ccc1O
Yield: 53.7 %

Procedure:
1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (3a, 0.55 g, 1.5 mmol) and palladium on activated carbon (0.25 g, 5%) were combined in ethyl acetate (30 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 4 hr at room temperature. The resulting mixture was filtered through celite and the solvent evaporated to afford a solid. The crude solid was recrystallized from ethyl acetate/hexane to give 0.30 g (54%) of white crystals: mp 92-94° C. [expected mp 92-93° C.]; 1H NMR: δ 2.53 (t, 4H, J=7.9 Hz), 2.83 (m, 4H), 3.84 (s, 6H), 5.40 (s, 1H), 5.48 (s, 2H), 6.64 (m, 4H), 6.81 (d, 2H, J=8.3 Hz), 15.44 (s, 1H); 13C NMR: δ 29.2, 31.3, 40.4, 45.5, 55.9, 99.7, 110.9, 111.0, 114.3, 120.7, 132.4, 143.9, 146.3, 193.0.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH:37]=[CH:36]2>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:44]3[CH2:45][CH2:46][N:41]([C:38]4[CH:37]=[CH:36][C:35]5[C:40](=[C:31]([Cl:30])[CH:32]=[CH:33][CH:34]=5)[N:39]=4)[CH2:42][CH2:43]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: Clc1cccc2ccc(N3CCNCC3)nc12
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ccc4cccc(Cl)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 8-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 94 %

Procedure:
To (66) (1.5 g) in ethanol (30 mL) was added sodium borohydride (1 g). After 4 h the reaction mixture was quenched with brine and the resulting solid was collected by filtration, and air dried to furnish 168 (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (1.42 g).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][CH2:19]O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CCN(S(F)(F)[F:27])CC.ClCCl>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][CH2:19][F:27])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2CCC(OCCCO)CC2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(OCCCF)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
A mixture of 2.75 g (9.8 mmol) of 4-(4-propylcyclohexyl)-(3-hydroxypropyloxy)cyclohexane obtained in Example 4, 3.14 g (19.6 mmol) of DAST, and 25 ml of dichloromethane was stirred for 5 hours at a room temperature. The reaction product was put in 40 ml of an ice water and extracted with 40 ml of toluene. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The magnesium sulfate was separated, the solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to a silica gel column chromatography (eluate: toluene) to obtain 1.87 g of a crude 4-(4-propylcyclohexyl)-(3-fluoropropyloxy) cyclohexane. This product was recrystallized twice from 6 ml of ethanol in a freezer to obtain 1.60 g (yield 58%) of 4-(4-propylcyclohexyl)-(3-fluoropropyloxy)cyclohexane. Several kinds of spectra well supported its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@@H:36]([F:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:9][N:10]([CH2:18][CH:19]2[CH2:21][CH2:20]2)C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:41]>O1CCOCC1>[ClH:1].[ClH:41].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[C:31]4[C@H:38]([CH3:39])[CH2:37][C@@H:36]([F:40])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:28][CH2:29]2)=[O:23])=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@H](CN(CC4CC4)C(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@H](CNCC4CC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate (0.955 g, 1.669 mmol) was dissolved in dioxane (20 mL). The solution was treated with HCl in dioxane (10.43 mL, 41.73 mmol; 4M), and the mixture was stirred at ambient temperature for 16 hours. HPLC showed no SM remaining, so the reaction mixture was concentrated in vacuo, re-dissolved in MeOH and re-concentrated (3×). The residue was re-dissolved in MeOH (about 4.5 mL+2 mL wash) and added dropwise to stirred ether (about 190 mL). The suspension was stirred for 30 minutes then filtered and dried under nitrogen blanket to give (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (797 mg, 88%) as a solid. LC/MS (APCI+, FIA) m/z 472.2/474.2 [M+H]+