Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH:12]([CH3:24])[C:11]=2[NH:10][C:9](=[O:25])[CH:8]=1>CN(C=O)C>[Br:3][C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH:12]([CH3:24])[C:11]=2[NH:10][C:9](=[O:25])[CH:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2c(O)cc(=O)[nH]c21
Solvent: CN(C)C=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2c(Br)cc(=O)[nH]c21
Temperature: 90 °C
Yield: 50 %

Procedure:
TFA (9.20 mmol, 0.709 ml) was slowly added to a stirred solution of tert-butyl 4-hydroxy-9-methyl-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.541 g, 1.84 mmol) in DCM (20 ml) at room temperature. The reaction solution was stirred until all starting materials are consumed. The solvent was removed under reduced pressure and the resulting residue was dissolved in DCM (20 ml). Addition of Et3N (18.4 mmol, 2.56 ml) and TFAA (3.86 mmol, 0.511 ml) was followed by stirring for 8 h at room temperature. The reaction mixture was parted between sat. aq. NaHCO3 and DCM. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified to provide 277 mg (52%, two steps) of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 291 [M+1]+. POBr3 (0.533 mol, 153 mg) was added to a stirred solution of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (77 mg, 266 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 2 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 47 mg (50%) of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 353/355. A mixture of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (47 mg, 134 μmol), EtOH (2 ml) and 10% Pd/C was stirred for 5 minutes under H2 atmosphere (1 atm). The reaction was filtered through Celite and 35 mg (99%) of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one was obtained. MS (ESI) m/z 275. POBr3 (256 μmol, 73.5 mg) was added to a stirred solution of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (35 mg, 128 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 5 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 24 mg (56%) of 2-bromo-9-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 337/339. Deprotection was carried out at 60° C. for 10 minutes using MeOH (1 ml), H2O (200 μl) and K2CO3 (30 mg) to render 15 mg (87%) of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.42 (d, 1H), 7.35 (d, 1H), 4.25 (m, 2H), 3.86 (m, 2H), 3.18 (m, 2H), 2.84 (dd, 1H), 1.21 (d, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[N:4][C:5]([N:10]3[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCN[C@H](C)C2)c1C
Temperature: 110 °C
Yield: 77.2 %

Procedure:
To a round bottom flask is added 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (500 mg, 2.07 mmol), 4-fluorophenylboronic acid (580 mg, 4.15 mmol) sodium carbonate (440 mg, 4.15 mmol), toluene (16 mL) and water (8 mL). The reaction mixture is purged with nitrogen for 20 min. Tetrakis(triphenylphosphine) palladium (50 mg, 0.103 mmol) is added and the mixture is heated to 110° C. for 18 h. The reaction mixture is concentrated and partitioned between ethylacetate and water. It is extracted with ethylacetate twice and the combined organic phases are dried with sodium sulfate and concentrated. It is purified by column chromatography (0-25% methanol/methylene chloride) to give 480 mg of 3-(4-fluoro-phenyl)-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (83%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:15]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C@H:11]([O:12][CH3:13])[C@@H:10]1[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:31][C@@H:10]1[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@:15]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:14][CH:11]1[O:12][CH3:13])(=[O:34])[CH3:33]
Reactant: CO[C@H]1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
To a stirred solution of 201 (687 mg, 1.52 mmol) in anhydrous pyridine (4 mL) at 0° C. was added dropwise acetic anhydride (0.43 mL, 4.56 mmol). The reaction mixture was stirred for 2 days at room temperature, quenched with saturated aqueous sodium hydrogen carbonate (75 mL) and extracted with dichloromethane (150+75 mL). The combined extract was dried (MgSO4), the solvent was removed by distillation under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane as eluent to give the product 209 as a clear oil (β:α˜3:1, 750 mg, 100%); MS FAB: 463 (M−OCH3, 100%), 517 (M+Na, 28%); Found: C, 58.53; H, 6.16. C24H30O9S requires C, 58.29; H, 6.11%. Methyl 2-O-acetyl-3,5-di-O-benzyl-4-C-methanesulfonyloxymethyl-β-D-ribofuranoside (209β). 1H NMR (CDCl3): δ 7.36-7.18 (10 H, m, Bn), 5.27 (1 H, d, J 4.9 Hz, H-2), 4.88 (1 H, s, H-1), 4.55-4.44 (6 H, m, H-5′, Bn), 4.35 (1 H, d, J 5.0 Hz, H-3), 3.73 (1 H, d, J 9.2 Hz, H-5), 3.38 (1 H, d, J 9.3 Hz, H-5), 3.30 (3 H, s, OCH3), 2.95 (3 H, s, SO2CH3), 2.11 (3 H, s, OCCH3); 13C NMR (CDCl3): δ 169.91 (C═O), 137.83, 137.28, 128.49, 128.44, 127.99, 127.87, 127.77 (Bn), 105.40 (C-1), 82.65, 81.05, 74.55, 73.62, 73.56, 71.86, 70.22 (C-2, C-3, C-4, C-5, C-5′, Bn), 55.03 (OCH3), 37.14 (SO2CH3), 20.73 (OCCHa). Methyl 2-O-acetyl-3,5-di-O-benzyl-4-C-methanesulfonyloxymethyl-α-D-ribofuranoside (209α). 1H NMR (CDCl3): δ 7.36-7.18 (10 H, m, Bn), 5.09 (1 H, d, J 4.5 Hz, H-1), 4.95 (1 H, dd, J 4.5, 6.8 Hz, H-2), 4.65-4.44 (6 H, m, H-5′, Bn), 4.27 (1 H, d, J 6.6 Hz, H-3), 3.49 (1 H, d, J 9.9 Hz, H-5), 3.46 (3 H, s, OCH3), 3.36 (1 H, d, J 9.9 Hz, H-5), 2.92 (3 H, s, SO2CH3), 2.14 (3 H, s, OCCH3): 13C NMR (CDCl3): δ 170.41 (C═O), 137.59, 137.28, 128.56, 128.51, 128.49, 128.44, 127.98, 127.88 (Bn), 102.35 (C-1), 84.25, 77.53, 74.66, 73.67, 72.12, 70.39, 70.28 (C-2, C-3, C-4, C-5, C-5′, Bn), 56.07 (OCH3), 36.94 (SO2CH3), 20.63 (OCCH3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][CH2:8][N:9]1[CH2:29][CH2:28][C:12]2([O:17][CH2:16][CH2:15][N:14]([C:18]([C:20]3[N:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[S:23][CH:24]=3)=[O:19])[CH2:13]2)[CH2:11][CH2:10]1.[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[CH:34]=[CH2:35].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(#N)C>[CH:25]([C:22]1[S:23][CH:24]=[C:20]([C:18]([N:14]2[CH2:13][C:12]3([CH2:28][CH2:29][N:9]([CH2:8][CH2:7][C:6]4[CH:5]=[C:4]([CH:32]=[CH:31][CH:30]=4)[CH2:3][CH2:2][O:1][CH2:35][CH2:34][C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH2:11]3)[O:17][CH2:16][CH2:15]2)=[O:19])[N:21]=1)([CH3:27])[CH3:26]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCO)c4)CC3)C2)cs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(9-(3-(2-Hydroxyethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone [Example 34, step a] (2.4 g) was dissolved in acetonitrile (2 mL) and tert-butyl acrylate (1.7 mL) added, followed by benzyltrimethylammonium hydroxide (40% in water, 0.72 mL). The mixture was stirred at ambient temperature for 3 hours. The volatiles were removed under reduced pressure and the residue purified by flash silica chromatography eluting with 3% methanol in dichloromethane containing 1% ‘880’ aqueous ammonia to afford the subtitled compound Yield 2.7 g.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][CH:23]=[CH:22]2>>[NH2:14][C:13]1[O:16][CH:17]2[C:25]3[C:21](=[CH:20][CH:19]=[C:18]2[CH:1]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:8]#[N:9])[CH:10]=2)[C:12]=1[C:11]#[N:15])[CH:22]=[CH:23][N:24]=3
Reactant: N#Cc1cncc(C=O)c1
Reactant: Oc1cccc2cc[nH]c12
Reactant: N#CCC#N
Product: N#CC1=C(N)OC2C(=CC=C3C=CN=C32)C1c1cncc(C#N)c1
Yield: 59 %

Procedure:
The title compound was prepared from 5-formyl-nicotinonitrile, malononitrile and 7-hydroxyindole by a procedure similar to Example 57 in 59% yield. 1H-NMR (Acetone-d6): 10.54 (brs, 1H), 8.84 (m, J=2.20, 1.90 Hz, 2H), 8.12 (t, J=2.20, 1.90 Hz, 1H), 7.39 (m, J=3.03 Hz, 1H), 7.32 (dd, J=8.00 Hz, 1H), 6.68 (dd, J=8.20 Hz, 1H), 6.51 (m, J=3.03 Hz, 1H), 6.22 (s, 2H), 5.13 (s, 1H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1.[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:16][CH:13]1[CH2:15][CH2:14]1)[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:23]
Reactant: NCC1CC1
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Product: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 66.5 %

Procedure:
3.6 g of D-galactose, 2.2 g of cyclopropylmethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 23-(1). 4.5 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-galactopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: C([Li])(C)(C)C.I[C:7]1([CH2:10][C@H:11]2[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]2)[CH2:9][CH2:8]1.[S:18]([Cl:21])(Cl)=[O:19].CC[O:24]CC>>[CH3:16][C:13]1([CH3:17])[O:12][C@@H:11]([CH2:10][C:7]2([S:18]([Cl:21])(=[O:19])=[O:24])[CH2:9][CH2:8]2)[CH2:15][O:14]1
Reactant: CC1(C)OC[C@H](CC2(I)CC2)O1
Reactant: CCOCC
Reactant: O=S(Cl)Cl
Agent: [Li]C(C)(C)C
Product: CC1(C)OC[C@H](CC2(S(=O)(=O)Cl)CC2)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl lithium (2 eq) is added to a solution of (S)-4-((1-iodocyclopropyl)methyl)-2,2-dimethyl-1,3-dioxolane (1 eq) in ether at −78° C. and the mixture stirred at −78° C. for 30 mins. A solution of thionyl chloride in ether is added, the mixture warmed to room temperature and concentrated under reduced pressure. The residue is dissolved in chloroform, filtered and dried under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=O)[CH3:26])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: COc1ccc(CCC(C)=O)cc1
Product: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-methoxy-phenyl)-butan-2-one.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:30][CH2:31]1)[CH3:19]
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: CCc1ccccc1N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-ethyl-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(2-ethyl-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=412.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9](=[CH:15][C:16]2[O:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:5][CH:4]=1.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>CCCCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]2[N:24]=[C:25]3[NH:26][N:27]=[C:28]([CH3:30])[C:29]3=[C:15]([C:16]3[O:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=O)C(=Cc1ccc(C)o1)C(=O)c1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCO
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(C)c2c1-c1ccc(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
A mixture of 0.76 g (2.41 mmol) of ethyl 2-(4-methoxybenzoyl)-3-(5-methylfuran-2-yl)acrylate and of 0.23 g (2.41 mmol) of 3-amino-5-methyl-pyrazole is heated to 140° C. in 6 ml of n-BuOH for 24 h. The mixture is then cooled to room temperature and 0.55 g (2.4 mmol) of DDQ in 6 ml of THF is added. The mixture is stirred at room temperature for 1 h. The mixture is then poured onto a saturated solution of NaHCO3 then extracted with ethyl acetate. The organic phase is washed in a saturated solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated. The mixture is then purified using reverse-phase HPLC to yield 146 mg (15%) of ethyl 6-(4-methoxyphenyl)-3-methyl-4-(5-methylfuran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow solid.
Reaction SMILES: C1COCC1.[C:6]1([C:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO>C1(C)C=CC=CC=1>[C:6]1([C@H:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[OH:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cn1nccc1C(=O)c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1nccc1[C@H](O)c1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazaborole 1M in toluene (7.5 ml, 7.5 mmol) cooled to -10° C., under an argon atmosphere, a solution of catecolborane 1M in THF (100 ml, 100 mmol) is added dropwise. To the resulting mixture a solution of phenyl-(1-methyl-1H-pyrazol-5-yl)ketone, III (9.30 g, 50 mmol) in dry toluene is added. Once the addition has been completed the mixture is stirred for 1 hour at -10° C. and then over night at room temperature. Next, MeOH (10 ml) is carefully added while stirring, which is maintained for 6 hours. The reaction mixture is concentrated to half the volume, washed successively with water and with a solution of saturated NaCl, dried and the solvent evaporated to yield an oil which is purified on a silicagel column, eluted with a mixture of ethyl acetate: petrol ether (7:3) to give (R)-(+)-phenyl-(1-methyl-1H-pyrazol-5-yl)methanol, (+)-II (7.82 g, 83%), whose optical purity as determined by chiral HPLC is 99%. M.p. 81-83° C.; [α]D =+16.6 (c=1.0, CHCl3).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[NH2:6][C:7]1[N:12]=[C:11](O)[C:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:9]([CH3:33])[N:8]=1>>[NH2:6][C:7]1[N:12]=[C:11]([Cl:3])[C:10]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:9]([CH3:33])[N:8]=1
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(OCc2ccccc2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
POCl3 (25 ml) was added to the product from step (vi) (4.8 g) and stirred at 80° C. for 18 h. After cooling, the reaction was evaporated to dryness and the residue diluted with water (100 mL) and neutralized with solid NaHCO3. The mixture was heated at 50° C. for 30 min and left to cool. The subtitle compound was collected by filtration as a solid, 3.78 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[CH:32]1([C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[N:36]([C:2]3[CH:3]=[CH:4][C:5]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:6]([C:8]([N:10]4[CH2:15][CH2:14][N:13]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)[CH2:12][CH2:11]4)=[O:9])[CH:7]=3)[CH:37]=[CH:38][N:39]=2)[CH2:34][CH2:33]1
Reactant: c1c[nH]c(C2CC2)n1
Reactant: O=C(c1cc(Br)ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Product: O=C(c1cc(-n2ccnc2C2CC2)ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 16 %

Procedure:
The title compound was prepared according to the procedure described for example 199 from (5-Bromo-2-morpholin-4-yl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CR) and 2-Cyclopropyl-1H-imidazole (CAS: 89532-38-7) (16% yield, white solid, MS (m/e): 526.3 (M+H, 100%)
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29](Cl)=[O:30]>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29]([C:11]1[C:12]2[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=2[N:9]2[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=12)=[O:30]
Reactant: CC(C(=O)[O-])C1CCn2c1cc1c(Br)cc(F)cc12
Reactant: O=C(Cl)c1nc2ccccc2s1
Product: O=C(O)CC1CCn2c1c(C(=O)c1nc3ccccc3s1)c1c(Br)cc(F)cc12

Procedure:
Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 7, Step 8) and 1,3-benzothiazole-2-carbonyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[S:10][C:9]([C:11](=[NH:13])[NH2:12])=[N:8][CH:7]=1.[Br:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Br:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([CH3:32])[NH:12][C:11]([C:9]2[S:10][C:6]([F:5])=[CH:7][N:8]=2)=[N:13]1
Reactant: N=C(N)c1ncc(F)s1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Br
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Yield: 44.4 %

Procedure:
5-fluorothiazole-2-carboximidamide acetate (0.22 g, 1.07 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (0.22 g, 1.07 mmol) and ethyl 3-oxobutanoate (0.14 g, 1.07 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (0.21 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23]>C(Cl)(Cl)Cl.CO>[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.5 in 9:1 CHCl3/MeOH).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5](I)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]([C:14]#[N:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cnc2cccc(I)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1cnc2cccc(C#N)c2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
A suspension of 2-methyl-8-iodoquinoxaline (730 mg), Zn(CN)2 (423 mg) and Pd(PPh3)4 (313 mg) in DMF (5 mL) was stirred at 60° C. for 5 hours. The reaction solution was cooled, and thereto was added water (10 mL), and the mixture was extracted twice with a mixture of toluene and ethyl acetate (1:1) (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→4/1) to give 2-methyl-8-cyano-quinoxaline (422 mg, 93%) as red brown solid.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)=[O:23])=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CO.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[C:15]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)=[O:23])=[CH:14][N:13]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CCOC(=O)C1CCN(C(=O)c2cnc(NC34CC5CC(CC(C5)C3)C4)nc2C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(C(=O)c2cnc(NC34CC5CC(CC(C5)C3)C4)nc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 1-{[2-(adamantan-1-ylamino)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}piperidine-4-carboxylate (220 mg), methanol (3 mL) and tetrahydrofuran (3 mL) was added a 1 M aqueous sodium hydroxide solution (1.37 mL) at room temperature, followed by stirring at 60° C. for 2 hours. To the reaction mixture were added 1 M hydrochloric acid and water, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, to the obtained residue was added water, followed by stirring for 30 minutes, and then the precipitate was collected by filtration and washed with water to obtain 1-{[2-(adamantan-1-ylamino)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}piperidine-4-carboxylic acid (190 mg) as a white powder.