Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[N:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:21](O)=[O:22])[C:5]2=[N:6][CH:7]=1.[F:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[N:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:21]([NH:27][CH2:26][CH2:25][F:24])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: NCCF
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(Br)cc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NCCF)c3ncc(Br)cc32)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
See FIG. 20(d). To a stirred solution of 6-bromo-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.13 g, 0.34 mmol) in dichloromethane (10 mL), were added 2-fluoroethan-1-amine (0.06 g, 0.68 mmol), triethylamine (0.1 g, 1.02 mmol) and T3P (0.32 g, 1.02 mmol) and the mixture was stirred at RT for 16 h. Then the reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine and concentrated. The crude product was purified by silica gel column chromatography and subsequent PREP purification to afford 6-bromo-N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide as a white solid. Yield: 25 mg (17%). ES+MS m/z: 424.2 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.24 (s, 3H), 3.68 (bs, 1H), 3.75 (bs, 1H), 4.51 (bs, 1H), 4.64 (bs, 1H), 5.70 (s, 2H), 8.28 (s, 1H), 8.39 (d, 1H, J=10.9 Hz), 8.58 (s, 1H), 8.64 (bs, 2H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].C(OCC)(=O)C>[N+](C)([O-])=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: N#CCOc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: N#CCOc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
A solution of 7.5 g of (4-hydroxy-phenoxy)-acetonitrile dissolved in 60 ml of nitromethane was cooled in an ice bath and 3.88 ml of 70% nitric acid was added dropwise. After 45 minutes, the reaction mixture was poured into ethyl acetate, washed with brine, dried (MgSO4), and evaporated to dryness. The crude product was purified by silica gel chromatography eluting with ethyl acetate/hexane (1:3), giving 5.45 g of (4-hydroxy-3-nitro-phenoxy)-acetonitrile as a yellow solid, mp 113.1-114.1° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:20]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])=[O:21])[CH3:19])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C.Br>CCOCC>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:20]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])=[O:21])[CH3:19])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.50 g of Z-Leu-Leu-Ala-Gln-OH was added 20 ml of acetic acid containing 25% of hydrogen bromide, then the mixture was stirred at a room temperature for 1 hour. To the reaction mixture was added dried ether, and solid material precipitated was collected by filtration to obtain H-Leu-Leu-Ala-Gln-OH.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].C([Li])CCC.C(NC(C)C)(C)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[NH:31][C:30](=[O:32])[CH:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:26]=2[CH:45]=1.ICC.C(=O)=O.C(Cl)(Cl)(Cl)Cl>O1CCCC1.CCCCCC.CN(C)P(=O)(N(C)C)N(C)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[NH:31][C:30](=[O:32])[C:29]([CH2:1][CH3:2])([C:33]([O:35][CH3:36])=[O:34])[CH:28]([C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[CH2:27][C:26]=2[CH:45]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: O=C=O
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(C(=O)OC)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a freshly prepared solution of lithium diisopropylamide in tetrahydrofuran (6 equivalents; prepared by addition of 19.2 ml of a 2.6M solution of n-butyllithium in hexane to 15 ml of freshly distilled diisopropylamine in 80 ml of tetrahydrofuran) at -78° C., was added 3.0 g (8.35 mmole) of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (see Example 1C . After stirring at -78° C. for 1.5 hours, 3 ml of hexamethylphosphoric triamide was added along with 13.6 ml of iodoethane (filtered through alumina to remove iodine). The mixture was stirred at -78° C. for 30 minutes (under argon), and then at -20° C. (dry-ice/carbon tetrachloride bath) for six days. The reaction was quenched with 1N hydrochloric acid (50 ml), and the aqueous layer was extracted with ethyl acetate (three times). The ethyl acetate extracts and the tetrahydrofuran were combined, washed with saturated sodium bicarbonate and saturated sodium chloride, and dried (magnesium sulfate). The solution was concentrated, combined with 0.31 g of previously prepared crude product and flash chromatographed (silica gel/3:1-hexane:ethyl acetate) yielding 0.61 g of product.
Reaction SMILES: F[C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:23][S-:24].[Na+]>CS(C)=O>[CH3:23][S:24][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: O=C(O)c1cccc2nc3ccc4c(F)cccc4c3nc12
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1cccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Temperature: 130 °C

Procedure:
To a stirred solution of 4-fluoro-benzo[a]phenazine-11-carboxylic acid (II.3, see Reference Example 1B (58 mg) in dry DMSO (3 mL) was added sodium thiomethoxide (55 mg) and the reaction mixture heated at 100° C. for 1.5 hours and 130° C. for 1 hour. The reaction mixture was then cooled to room temperature, quenched with acetic acid, extracted with ethyl acetate, washed with water, dried and the solvent removed in vacuo to yield the title compound as a red solid (37 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[CH2:9]P(=O)(OCC)OCC)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[CH3:28][O:29][C:30]1[C:35]([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]2)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCCC1>[CH3:28][O:29][C:30]1[C:35]([CH2:36][N:37]2[CH2:42][CH2:41][CH:40](/[CH:43]=[CH:9]/[C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:39][CH2:38]2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: COc1ncccc1CN1CCC(C=O)CC1
Reactant: CCOP(=O)(Cc1ccccc1OC1CCCC1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ncccc1CN1CCC(/C=C/c2ccccc2OC2CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
786 mg of diethyl 2-(cyclopentyloxy)benzylphosphonate was dissolved in 10 ml of tetrahydrofuran. To the mixture was added 281 mg of potassium tert-butoxide, followed by stirring for 15 minutes under ice-cooling. A solution of 500 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-piperidinecarboxaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise thereinto, followed by stirring at room temperature for 2 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to give 473 mg of the title compound as a pale yellow oil.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]3[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=3)[CH2:54][CH2:53]2)=[C:35]2[N:41]=[C:40]([CH2:42][CH2:43][NH:44]C(=O)OC(C)(C)C)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]3[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=3)[CH2:54][CH2:53]2)=[C:35]2[N:41]=[C:40]([CH2:42][CH2:43][NH2:44])[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NCCc1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Yield: 62.1 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 2-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)ethylcarbamate (20 mg, 0.058 mmol), TFA (0.2 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (15 mg, 93%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.58 (s, br, 4H, piperazine N(CH2)2), 2.87 (t, J=6.7 Hz, 2H, CH2CH2NH2), 3.00 (t, J=6.8 Hz, 2H, CH2CH2NH2), 3.55 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2Ar), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.77 (d, br, J=7.8 Hz, 1H, pyridine H-4), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 4.49 (dd, J=4.7, 1.0 Hz, 1H, pyridine H-6), 8.55 (d, J=1.1 Hz, 1H, pyridine H-2);
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:10]1[CH3:20]>ClCCl>[CH3:20][C:10]1[N:9]([CH2:8][CH2:7][OH:6])[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1
Reactant: COCCn1cc(-c2ccccc2)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)cn1CCO
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Boron tribromide (0.3 mL, 3.07 mmol) was added drop wise to a solution of 1-(2-methoxyethyl)-2-methyl-4-phenyl-pyrrole (330 mg, 1.53 mmol) in dry dichloromethane (20 mL) at 0 to 5° C. and stirred for 1 h. The reaction mixture was quenched with a 10% sodium bicarbonate solution (20 mL) at 0 to 5° C. and extracted with ethyl acetate (2×25 mL). The organic layer was washed successively with water (2×25 mL), brine (2×25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to yield 2-(2-methyl-4-phenyl-pyrrol-1-yl)-ethanol (270 mg, 88%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CC.C[O-].[Na+].C(O)C>C1(C)C=CC=CC=1>[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:9][CH2:8][O:7][C:5]([CH:4]([N:2]([CH3:3])[CH3:1])[CH3:10])=[O:6]
Reactant: CCOC(=O)C(C)N(C)C
Reactant: CCCCCCCCCCCCO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCOC(=O)C(C)N(C)C

Procedure:
DDAIP was prepared by transesterification of ethyl 2-(N,N-dimethylamino)-propionate obtained from Varsal Instruments Inc. (Warminster, Pa). Specifically, a mixture ethyl 2-(N,N-dimethylamino)-propionate, 1-dodecanol, and sodium methoxide predissolved in toluene was refluxed for about 2 hours. As ethanol formed, it was removed by azeotropic distillation. After about 2 hours of refluxing, the remaining reaction product was filtered to remove solids.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]([N:19]1[CH2:23][C:22](=O)[N:21]=[CH:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: Cc1cc(N)n(-c2ccc(Cl)c(Cl)c2)n1
Reactant: CC(=O)N1C=NC(=O)C1
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccc(Cl)c(Cl)c1

Procedure:
5-Amino-3-methyl-1-(3,4-dichlorophenyl) pyrazole (16.6 g.) and 1-acetyl-2-imidazolinone (10.6 g.) were reacted as described in Example I to give 8.5 g. of product, mp 156°-157°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>C(OCC)C>[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(N=C=O)cc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Agent: [Na]
Solvent: CCOCC
Product: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1
Reaction time: 0.03 h
Yield: 87 %

Procedure:
To a solution of 1-benzylindolin-5-ol (1.50 g, 6.66 mmol) in 33 mL of diethyl ether (5 mL/mmol) was added a piece of sodium (1 mg to 10 mg) at room temperature. After the reaction mixture was stirred at the same temperature for 2 min, 4-isopropylphenylisocyanate (1.3 mL, 8.0 mmol, 1.2 equivalent) was added with additional stirring for 5 min to 10 min. After removal of sodium, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 0/100) to obtain the title compound (2.24 g, 87%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:28]=[CH:27][C:11]([CH2:12][N:13]2[C:17]3=[N:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=[C:16]3[N:15]=[C:14]2[CH3:26])=[C:10]([Cl:29])[CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:28]=[CH:27][C:11]=1[CH2:12][N:13]1[C:17]2=[N:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[CH3:26]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)CCCBr)cc3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N4CCCC4=O)cc3Cl)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Methyl 3-(4-((4-bromobutyryl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (425 mg) was dissolved in N,N-dimethylformamide (5 ml) and potassium carbonate (245 mg) was added, which was followed by stirring at 60° C. for 2 hr. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (10 ml) was added to the residue, and the mixture was heated and allowed to cool. The precipitated crystals were collected by filtration and dried under reduced pressure with heating to give methyl 3-(2-chloro-4-(2-oxotetrahydro-1H-pyrrol-1-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (235 mg) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10](I)=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].[NH4+].[Cl-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1C#C[Si](C)(C)C
Temperature: 32 °C
Reaction time: 4 h

Procedure:
Under a stream of Ar the above prepared (5-iodo-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.913 g, 2.68 mmol) was dissolved in 17 mL of acetonitrile and treated successively with triethylamine (1.12 mL, 3 eq.), Cul (0.051 g, 0.1 eq.), (Ph3P)2PdCl2 (0.188 g, 0.1 eq.), and ethynyltrimethylsilane (1.11 mL, 3 eq.). The flask was closed with a septum and allowed to stir for 4 h at 32° C. The reaction mixture was then poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/ethyl acetate=85/15) gave finally 0.592 g of the title compound as light brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](Cl)=[N:33][CH:32]=1.C(N(CC)CC)C.N12CCN(CC1)CC2>CN(C=O)C.O>[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:33][CH:32]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nc1
Reaction time: 0.17 h
Yield: 16 %

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (150 mg, obtained in Example 172) was added to a solution of methyl-6-chloro-nicotinate (64 mg, [CAS Reg. No. 73781-91-6]) in DMF (1.9 mL) followed by the addition of triethylamine (0.067 mL). Stirring was continued for 10 minutes at r.t. Then 1,4-diazabicyclo[2.2.2]octane (6 mg) was added. The mixture was stirred over night at r.t. and then 4 hours at 60° C. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the desired compound as a colorless foam (33 mg, 16%). MS (m/e)=537.2 [M+H+].
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[C:9](=[O:27])[N:10]3[CH2:26][CH2:25][CH2:24][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:8]2[C:9](=[O:27])[N:10]3[CH2:26][CH2:25][CH2:24][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:36]
Reactant: CSc1cccc2c1C(=O)N1CCC[C@H]1c1c(C(=O)OC(C)(C)C)ncn1-2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)c1cccc2c1C(=O)N1CCC[C@H]1c1c(C(=O)OC(C)(C)C)ncn1-2
Reaction time: 8 h

Procedure:
4.0 g (10.38 mmol) of t-butyl (S)-11,12,13,13a-tetrahydro-8-methylthio-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate are dissolved in 25 ml of methylene chloride, treated portionwise at room temperature with 2.0 g (about 10.4 mmol) of about 90% percent m-chloroperbenzoic acid and left to stand at room temperature overnight. Then, the solution is poured into 2 N sodium hydroxide, the methylene chloride phase is separated, dried over magnesium sulphate and evaporated. After recrystallization from ethyl acetate/hexane, there is obtained t-butyl (S)-11,12,13,13a-tetrahydro-8-methylsulphinyl-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 224°-225° as a diastereoisomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a stirred solution of Intermediate 53 (120 mg) in a mixture of methanol (1.5 mL) and dichloromethane (1.5 mL) at ambient temperature was added sodium borohydride (30 mg) in one charge. The reaction was stirred at ambient temperature under an atmosphere of nitrogen for 2 hr. The reaction was partitioned between ethyl acetate (20 mL) and water (20 mL). The organics were dried (hydrophobic frit) and concentrated in vacuo to give the title compound (85 mg). LC/MS MH+ 319, Rt 1.92 min (5 min run).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Br)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14](=[S:19])([O:16]CC)[NH2:15].CC(N(C)C)=O>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[NH:15][C:14](=[O:16])[S:19][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: CCOC(N)=S
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(=NOC)c1csc(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (7.6 g.), O-ethyl thiocarbamate (3.0 g.) and dimethylacetamide (5 ml.) was stirred for 3 hours at 50° C. Ethyl acetate (50 ml.) was added to the reaction mixture and the resulting mixture was washed with water and with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. Ethyl acetate was distilled off to give crystalline residue. The residue was washed with diisopropyl ether to give ethyl 2-methoxyimino-2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate (syn isomer) (2.35 g.).
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[CH2:40]([NH:43][C:44](=[O:51])[C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1)[C:41]#[CH:42]>CN(C=O)C.[Cu]I>[Cl:29][C:27]1[CH:28]=[C:23]([C:17]2([C:19]([F:22])([F:20])[F:21])[O:16][N:15]=[C:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([N:1]4[CH:42]=[C:41]([CH2:40][NH:43][C:44](=[O:51])[C:45]5[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=5)[N:3]=[N:2]4)=[CH:5][CH:6]=3)[CH2:18]2)[CH:24]=[C:25]([Cl:30])[CH:26]=1
Reactant: [N-]=[N+]=Nc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: C#CCNC(=O)c1ccncc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cn(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)nn1)c1ccncc1
Reaction time: 5 h

Procedure:
CuI (211 mg) is added to a solution of 3-(4-azido-naphthalen-1-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (500 mg), DIPEA (3.3 ml) and N-prop-2-ynyl-isonicotinamide (180 mg) in DMF (2.0 ml). After 5 hours at room temperature, the reaction is quenched with a saturated solution of NaHCO3 and extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and concentrated in mow. The crude product is purified on a semi-preparative HPLC to yield N-(1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-1H-[1,2,3]triazol-4-ylmethyl)-isonicotinamide as a colorless oil.