Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[OH:12][NH2:13].C([O-])([O-])=O.[K+].[K+]>CCO.CO>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:13][OH:12]
Reactant: O=Cc1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: ON=Cc1ccc(F)cc1F
Yield: 94.6 %

Procedure:
(Scheme 1, Compound C) To a mixture of 2,4-difluorobenzaldehyde (0.80 g, 5.6 mmol) and hydroxyamine HCl salt (0.43 g, 6.2 mmol) in EtOH (5 mL) was added K2CO3 (0.85 g, 6.2 mmol). The resultant mixture was stirred at rt for 24 hours. The mixture was diluted with MeOH (20 mL). The precipitates were filter off and washed with MeOH. The product from filtrate was purified by recrystalization (EtOAc/Hexanes). This compound was obtained as a white solid (0.84 g, 5.3 mmol, 94% yield). 1H NMR (DMSO-d6) δ 12.98 (br. s, 1H), 8.17 (s, 1H), 7.79 (m, 1H), 7.32 (m, 1H), 7.11 (m, 1H); Analytical HPLC 1.03 min. (95%); Mass Spec.: 158.06 (MH+).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]2=3)[CH2:19][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: O=c1ccsc2c3ccccc3n(CCN3CCOCC3)c12
Yield: 68 %

Procedure:
4.8 g of thiopyrano [3,2-b]indol-4-one and 15 g of chloroethylmorpholine, are reacted in the same manner as described in Example 14, except that the crude free base crystallized. This is filtered and recrystallized from methylenechloride-hexane to give 5.1 g of product, mp 136°-137° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].O>CS(C)=O>[NH2:3][C:4]1[C:9]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Nc1ncccc1O
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncccc1OCCCCCl
Reaction time: 0.25 h

Procedure:
To a suspension of 20 g (500 mmol) of 60% oily sodium hydride in 500 ml of dimethyl sulfoxide, 55.06 g (500 mmol) of 2-amino-3-hydroxypyridine was added at room temperature, followed by stirring for 15 minutes. To this mixture, 57.62 ml (500 mmol) of 1-bromo-4-chlorobutane was added, followed by stirring at 80° C. for 3 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: n-hexane/ethyl acetate=1/1→1/4→1/9). The resulting crude crystal was purified by recrystallization (solvent: chloroform-diethyl ether) to yield 10.35 g (10.3%, white crystal) of the desired product.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[NH:35]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36]1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:35]3[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36]3)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)N4CC[C@H](O)C4)c3n2)cn1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with (S)-pyrrolidin-3-ol via General Procedure F followed by Boc deprotection via General Procedure E to give 10.1 mg 110 as white solid following reverse phase purification. MS (Q1) 440.2 (M)+
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28](O)[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][O:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:15]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)n1ncc(OCc2ccc(COCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.4 %

Procedure:
To solution of the product of Example 3 (437 mg, 1.48 mmol) and 2-t-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (250 mg, 1.23 mmol) dissolved in anhydrous THF (12 mL) was added solid PPh3 (485 mg, 1.85 mmol) and diisopropyl azodicarboxylate (DIAD, 0.358 mL, 1.85 mmol). After completion of addition the reaction mixture continued to stir at room temperature. After 20 hours, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to provide the desired product 528 mg, 1.10 mmol) in 89% yield. 1H (CDCl3 7.70 (1H, s), 7.38 (4H, m), 5.30 (2H, s), 4.58, 600 MHz): δ (2H, s), 3.80 (2H, t, J=5.4 Hz), 3.57 (2H, t, J=5.4 Hz), 1.63 (9H, br s), 0.90 (9H, s), 0.07 (6H, s); 13C (CDCl3159.0, 153.7, 138.8, 134.4, 128.3, 127.3, 150 MHz): δ 125.1, 118.5, 72.8, 71.7, 71.6, 66.4, 61.9, 29.7, 27.9, 25.6, −5.1; HRMS calcd for C24H37ClN2O4Si: 481.228389, found 481.2282.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][N:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([CH:13]2[CH2:14][CH2:15]2)[C:11]1=[O:16])[CH3:23]
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]cc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reaction time: 8 h

Procedure:
740 mg (3.15 mmol) of 5-(4-chlorophenyl)-1-cyclopropyl-1,3-dihydro-2H-imidazol-2-one from Example 118A are dissolved in 15 ml acetonitrile and treated with 386 mg (3.15 mmol) of ethyl chloroacetate and 872 mg (6.31 mmol) of potassium carbonate. The mixture is stirred overnight under reflux. It is then concentrated, the residue is partitioned between dichloromethane and water, the organic phase is separated, and this is dried over sodium sulphate and again concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1→100:1) and thus yields 602 mg (57% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C1([O:23][C:24](=O)[NH:25][CH:26]([CH3:37])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:24]([NH:25][CH:26]([CH3:37])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[O:23])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: CC(Cc1c[nH]c2ccccc12)NC(=O)Oc1ccccc1
Solvent: C1COCCO1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)NC1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
The more polar diastereoisomer of N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine (109 mg, 0.5 mmole) was added to a solution of [2-(1H-indol-3-yl)-1-methyl-ethyl]-carbamic acid phenyl ester (147 mg, 0.5 mmole) in dioxane (10 ml). The batch was then refluxed for 6 h. Working up was performed by removing dioxane by distillation and diluting the batch with water (10 ml). The batch was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and evaporated. The more polar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexyl)-3-[2-(1H-indol-3-yl)-1-methylethyl]urea was obtained after chromatography on silica gel with methanol as a colorless oil in a yield of 100 mg (48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([O:34][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:36]=1
Reactant: COC(=O)CCCCCCCNc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)c1cccc(OCc2ccccc2)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCN(C(=O)c1cccc(OCc2ccccc2)c1)c1ccc(OCc2ccccc2)cc1

Procedure:
As described in example 3(b), the reaction is carried out with 4.7 g (13 mmol) of 8-(4-benzyloxyphenyl-amino)-caprylic acid methyl ester, 3.3 (13 mmol) of 3-benzyloxy- benzoic acid choride, 1.5 g (15 mmol) of triethylamine and 100 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([N:21]=[N+]=[N-])[C@H:11]([N:12]=[N+]=[N-])[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]>C(O)(=O)C.O.[C].[Pd]>[CH2:1]([O:3][C:4]([C@:6]1([NH2:21])[C@H:11]([NH2:12])[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N=[N+]=[N-])[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)[C@]1(N)[C@H](N)C[C@@H]2[C@H]1[C@@]2(F)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.4 %

Procedure:
25 mg of 10% palladium carbon was added to 170 mg of (1R,2R,3R,5R,6R)-2,3-diazido-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in a mixture of 15 mL of acetic acid and 5 mL of water, and the mixture was stirred for 24 hours at room temperature under a hydrogen atmosphere. After celite filturation, the solvent was distilled off at 50° C. under reduced pressure, thereby yielding 42 mg of (1R,2R,3R,5R,6R)-2,3-diamino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(OP([CH2:21][C:22]([OH:24])=[O:23])(OCC)=O)C.[NH2:25][C:26]1[C:27]2[C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:37][CH:36]=3)=[CH:33][N:32]([CH:48]3[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]3)[C:28]=2[N:29]=[CH:30][N:31]=1>O1CCCC1>[NH2:25][C:26]1[C:27]2[C:34]([C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:39][CH:40]=3)=[CH:33][N:32]([CH:48]3[CH2:53][CH2:52][C:51](=[CH:21][C:22]([OH:24])=[O:23])[CH2:50][CH2:49]3)[C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
A solution of diisopropylamine (1.40 g, 13.82 mmol) in tetrahydrofuran (60 mL) was added into a solution of 2.2 M n-BuLi (6.29 mL, 13.82 mmol) in tetrahydrofuran (20 mL) at −78° C. A solution of diethylphosphonoacetic acid (1.29 g, 6.59 mmol) in tetrahydrofuran (60 mL) was added at −78° C. under the atmosphere of nitrogen. The mixture was kept at −78° C. for 20 minutes and allowed to warm up to ambient temperature. The mixture was then transferred into a suspension of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (2.50 g, 6.28 mmol) in tetrahydrofuran (150 mL) at −78° C. quickly. The resulting mixture was allowed to warm up to ambient temperature overnight and the solvent was removed under reduced pressure. The residue was taken in water and adjusted PH to be 3-4 with 1M aqueous acetic acid followed by extraction with ethyl acetate three times. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyliden}acetic acid (1.96 g, 4.44 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.98(br, 1H), 7.45(d, 2H), 7.41(s, 1H), 7.40(d, 2H), 7.16(t, 1H), 7.08(m, 4H), 6.10(br, 2H), 5.70(s, 1H), 4.80(m, 1H), 2.50-1.90(m, 8H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.70 min. MS: MH+ 441.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH3:14]>>[F:10][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH2:11][CH2:12][CH2:13][CH3:14])[CH:21]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: CCCCOc1cccc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: CCCCOc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 39.1 %

Procedure:
The title compound (0.104 g) was prepared from 4-bromo-2,6-difluoroaniline (0.2 g, 0.96 mmol) and 3-butoxyphenylboronic acid (0.242 g, 1.2 mmol) as a colourless liquid.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[CH:3]=1.C([O-])(O)=O.[Na+].[NH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C.O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:18][CH2:19][C:20]([OH:22])=[O:21])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Br)cc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 4-bromo-2,5-dichloronitrobenzene (1.000 g, 3.691 mmol) in DMF (10.0 mL) at 65° C. was added dropwise a solution of NaHCO3 (0.316 g, 3.76 mmol) and glycine (0.280 g, 3.73 mmol, Aldrich, used as received) in water (3.8 mL). The resulting suspension was stirred at 65° C. for 65 h. The bright orange suspension was then cooled to r.t., filtered, washed with water (1.0 mL) and dried under vacuum to afford 0.284 g (98%, based on recovered starting material) of pure title compound as an orange powder; m.p. 264°-265° C. (decomposed); 1H NMR (DMSO-d6):3.451 (d, 2H, J=3.9 Hz), 7.199 (s, 1H), 8.130 (s, 1H), 8.793 (t, 1H, J=3.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[C:18](OC)(OC)(OC)[CH2:19][CH2:20][CH3:21]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:18]1[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(OC)(OC)OC
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Solvent: CC(=O)O
Product: CCCC1=Nc2ccccc2CC(c2sccc2C)N1C

Procedure:
A solution of 5.0 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine, 18.02 ml trimethyl orthobutyrate and 6.8 ml of glacial acetic acid was refluxed for 8 hours under a nitrogen atmosphere. The solution was concentrated at 40° C. on a rotary evaporator and the residual oil was acidified with 10% hydrochloric acid solution (60 ml) and extracted with diethyl ether (3×70 ml). The acidic aqueous phase was basified with 10% sodium hydroxide solution (100 ml) and extracted with diethyl ether (3×100 ml). The ethereal phase was dried over sodium sulfate/magnesium sulfate, filtered and concentrated to an oil. Purification was accomplished by HPLC (Water's Associates Prep LC/System 500A, silica gel, utilizing methanol followed by 2% triethylamine in methanol as successive eluents). Concentration of the appropriate fractions yielded 4,5-dihydro-3-methyl-4-(3-methyl-2-thienyl)-2-(1-propyl)-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([CH3:25])([O:20][Si](C)(C)C)[C:16]([F:19])([F:18])[F:17])=[C:7]([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:20])([CH3:25])[C:16]([F:18])([F:19])[F:17])=[C:7]([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH:8]=1
Reactant: COc1ccc(C(C)(O[Si](C)(C)C)C(F)(F)F)c(CCOC(C)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)(O)C(F)(F)F)c(CCOC(C)=O)c1
Reaction time: 1 h

Procedure:
To the crude reaction mixture described in example 2 containing a solution of acetic acid 2-[5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-ethyl ester was added tetrabutylammonium fluoride (52.9 mL of a 1.0M solution in tetrahydrofuran, 52.9 mmol). The reaction mixture was stirred one hour after which GC/MS and HPLC analysis showed no starting material. For characterization purposes, the reaction mixture was poured into water and extracted with methyl tert-butyl ether (75 mL). The organic layer was washed with water (75 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated to provide a crude oil. 1H NMR (400 MHz, CDCl3) δ1.82 (s, 3), 2.01 (s, 3), 2.98-3.06 (m, 2), 3.55 (dt, 1, J=13.7, 6.8), 3.79 (s, 3), 4.27-4.34 (m, 2), 6.73-6.77 (m, 2), 7.28 (d, 1, J=8.5). 13C NMR (100 MHz, CDCl3) δ20.92, 25.50, 34.16, 55.10, 66.49, 76.67 (q, J=30.3), 111.55, 118.25, 126.02 (q, J=286), 128.67, 129.56, 139.70, 159.20, 171.32. IR 3453, 1720, 1610, 1249, 1161, 1134, 1038 cm−1. Analysis calculated for C14H17F3O4: C, 54.90; H, 5.59. Found: C, 55.03; H, 5.85.
Reaction SMILES: Cl[B:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]1([Li])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C(OCC)C>[CH:10]1([B:2]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: [Li]C1C=Cc2ccccc21
Reactant: ClB(Cl)c1ccccc1
Solvent: CCOCC
Product: C1=CC(B(c2ccccc2)C2C=Cc3ccccc32)c2ccccc21
Temperature: 25 °C
Yield: 74.3 %

Procedure:
In 50 ml of diethyl ether, 5.01 g (31.5 mmol) of dichloro(phenyl)borane is cooled to -78° C. and a solution of 7.70 g (63.1 mmol) of indenyllithium in 50 ml of diethyl ether is added dropwise within one hour. After warming to room temperature, the mixture is filtered, and the slightly yellow filtrate is highly concentrated in vacuo. Gradual cooling from 0° C. to -20° C. results in the formation of 7.45 g (74%) of bis(indenyl) (phenyl)borane in the form of colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:18][C:19]([CH:23]1[CH2:25][CH2:24]1)([CH3:22])[C:20]#[N:21]>>[CH3:22][C:19]([NH:18][C:8]([C:5]1[CH:4]=[C:3]([O:11][C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([C:20]#[N:21])[CH:23]1[CH2:25][CH2:24]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1Br)C(F)(F)F
Reactant: CC(N)(C#N)C1CC1
Product: C[C@H](Oc1cc(C(=O)NC(C)(C#N)C2CC2)ncc1Br)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 96d) and 2-amino-2-cyclopropylpropanenitrile (CAN 37024-73-0) as starting materials and isolated (607 mg, 65%) as a yellow oil; MS (ESI, m/z): 420.4 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[F:27][C:28]([F:36])([F:35])[C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:22])([CH3:23])[C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:32]([C:29]3([C:28]([F:36])([F:35])[F:27])[CH2:31][CH2:30]3)=[O:33])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cccc(NC(=O)C3(C(F)(F)F)CC3)c2)N=C1N

Procedure:
The coupling of [(R)-4-(3-amino-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F1) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([N:11]4[CH:15]=[CH:14][N:13]=[N:12]4)=[N:9][CH:10]=3)[N:16]=2)[CH:19]=1
Reactant: O=C(CBr)c1ccc(-n2ccnn2)nc1
Reactant: Nc1ccc(I)cn1
Product: Ic1ccc2nc(-c3ccc(-n4ccnn4)nc3)cn2c1

Procedure:
The obtained 5-(2-bromoacetyl)-2-(1H-1,2,3-triazole-1-yl)pyridine is allowed to react with 2-amino-5-iodopyridine in accordance with known methods (for example, the method described in a literature, Zhi-Ping Zhuang et al., J. Med. Chem., 2003, 46, p. 237-243), to obtain 6-iodo-2-[2-(1H-1,2,3-triazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine (FIG. 1, step 3).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])(O)=O.[Na+].O.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: C1=CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOC(=O)N1CC=CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 3-pyrroline (3.5 gms) in ethanol (20 mL) was added ~25 mL saturated aq. NaHCO3 and enough water to allow rapid stirring. The mixture was cooled to 10° C. and allyl chloroformate (5.92 mL) was slowly added via pressure equalized addition funnel. The mixture was removed from ice bath and allowed to stir at room temperature for 2 hours. Product was extracted into Et2O (3×150 mL). The organic phase was washed with water (2×50 mL), dried (MgSO4) and solvent was evaporated at reduced pressure. Purification on silica (Et2O) afforded pure title compound.