Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C@H:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:27])=[CH:7][C:8]=1[C:14]([F:15])([F:16])[F:17])#[N:11]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized in manner similar to example 1 using 4-[(cyclopropylmethyl)amino]-2-(trifluoromethyl)benzonitrile and 1,1-dimethylethyl 2-bromopropanoate: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.6 Hz, 1H), 6.86 (dd, J=8.9, 2.7 Hz, 1H), 4.33 (q, J=7.1 Hz, 1H), 3.30 (m, 2H), 1.54 (d, J=7.1 Hz, 3H), 1.39 (s, 9H), 0.99 (m, 1H), 0.63 (m, 2H), 0.29 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:26][C:27]([C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=1)=[O:28].C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48]>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:11]1[C:12](=[N:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:4]=2)=[CH:10]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(Cl)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(Cl)c(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 75.4 %

Procedure:
In the same manner as in Reference Example 5 and using N-{2-chloro-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (364 mg, 0.711 mmol), N,N-diisopropylethylamine (161 μl, 0.924 mmol), iodoacetamide (171 mg, 0.924 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (305 mg, 75%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([O:25]C)=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:28])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Yield: 34.2 %

Procedure:
A solution of methyl 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)indolizine-8-carboxylate (30 mg, 0.066 mmol) and NaOH (14 mg, 0.33 mmol) in H2O-THF (1:1, 10 mL) was stirred at rt for 3 h. The mixture was acidified with 2 N HCl and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (10 mg; yield 34%) as a yellow solid. MS: m/z=442.7 (M+1, ESI+).
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].N([O-])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[OH:11][C@@H:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[C@H](O)C(=O)O
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To a solution of 30.0 g (0.229 mol) of L-tert-leucine in 345 mL of 1 N sulfuric acid, cooled to 0° C., was added over 2 h a solution of 23.7 g (0.343 mol) of sodium nitrite in 83 mL of water. The temperature was maintained below 5° C. during the addition, and the mixture was then refrigerated for 24 h. The solution was then extracted with 150 mL of ether (3×) and the extract was washed with 100 mL of saturated aqueous sodium chloride. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 19.5 g (65%) of a pale yellow oil. The crude product was taken to the next step. 1H-NMR (300 MHz, CDCl3): δ 3.91 (s, 1H), 1.01 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:49]=[CH:48][C:24]([C:25]([NH:27][S:28]([C:31]4[CH:36]=[CH:35][C:34]([NH:37][CH2:38][CH:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[C:33]([N+:45]([O-:47])=[O:46])[CH:32]=4)(=[O:30])=[O:29])=[O:26])=[C:23]([O:50][C:51]4[CH:52]=[C:53]5[C:57](=[CH:58][CH:59]=4)[NH:56][CH:55]=[CH:54]5)[CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:49]=[CH:48][C:24]([C:25]([NH:27][S:28]([C:31]4[CH:36]=[CH:35][C:34]([NH:37][CH2:38][CH:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[C:33]([N+:45]([O-:47])=[O:46])[CH:32]=4)(=[O:30])=[O:29])=[O:26])=[C:23]([O:50][C:51]4[CH:52]=[C:53]5[C:57](=[CH:58][CH:59]=4)[NH:56][CH2:55][CH2:54]5)[CH:22]=3)[CH2:19][CH2:20]2)=[CH:6][CH:7]=1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1Oc1ccc2c(c1)CCN2

Procedure:
A suspension of EXAMPLE 40D (22.57 mg) and sodium cyanoborohydride (25 mg) in acetic acid (5 ml) was stirred at room temperature for 2 hours. The product was partitioned between dichloromethane and water. The organic layer was separated, dried over Na2SO4, and concentrated. The crude product was purified by RP HPLC(C8, 30-100 acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.56 (s, 1H), 9.60 (s, 1H), 8.66 (t, 1H), 8.57 (d, 1H), 7.85 (dd, 1H), 7.71 (s, 1H), 7.46-7.60 (m, 5H), 7.29-7.42 (m, 3H), 7.25 (d, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 6.73 (d, 1H), 6.36 (s, 1H), 4.32 (bs, 2H), 3.85 (dd, 4H), 3.59 (t, 4H), 3.35 (t, 2H), 3.27 (t, 2H), 3.02 (t, 4H), 1.80-1.99 (m, 1H), 1.62 (d, 2H), 1.15-1.36 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:34]=[CH:33][CH:32]=[CH:31][C:8]=2[C:9]=1[C:10]([C:12]1[CH:13]=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([OH:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=[O:11])[CH2:2][CH2:3][CH3:4].Cl[S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[C:41]([OH:48])[CH:40]=1)(=[O:38])=[O:37]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:34]=[CH:33][CH:32]=[CH:31][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:24][S:36]([C:39]2[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[C:41]([OH:48])[CH:40]=2)(=[O:38])=[O:37])=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1

Procedure:
The title compound was prepared according to the procedure in Example 1, step 2, using (2-n-butyl-benzofuran-3-yl)-(2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-yl)-methanone (0.136 g, 0.305 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.144 g, 6.09 mmol) to give 0.080 g (38%) of the tide compound as a white solid, mp 190-197° C.; 1H NMR (DMSO-d6) δ0.77 (t, 3H), 1.22 (sextet, 2H), 1.63 (quintet, 2H), 2.83 (t, 2H), 6.55 (d, 1H), 6.66 (dd, 1H), 7.28-7.38 (m, 8H), 7.41-7.43 (m, 4H), 7.51 (dd, 1H), 7.57 (d, 1H), 7.64 (d, 1H), 7.74 (s, 2H). IR (KBr) 2900, 1675, 1390 and 1190 cm−1. mass spectrum (−ESI), m/z 645 (M−H). An al. Calcd. for C38H30O8S.2H2O: C, 66.85; H, 5.02; N, 0.00. Found: C, 66.80; H, 4.88; N, 0.07.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH2:7][C:8]1[O:12][C:11]([C:13]2[N:14]=[C:15]([NH:18][C:19]([NH:21]C(=O)C3C=CC=CC=3)=[S:20])[S:16][CH:17]=2)=[CH:10][CH:9]=1)(=[O:5])[CH3:4]>O.CO>[C:3]([NH:6][CH2:7][C:8]1[O:12][C:11]([C:13]2[N:14]=[C:15]([NH:18][C:19]([NH2:21])=[S:20])[S:16][CH:17]=2)=[CH:10][CH:9]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCc1ccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NCc1ccc(-c2csc(NC(N)=S)n2)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A solution of sodium hydroxide (0.55 g) in water (5 ml) was added to a suspension of 4-(5-acetylaminomethylfuran-2-yl)-2-(3-benzoylthioureido)thiazole (5.40 g) in methanol (50 ml) and the mixture was stirred at 60° C. for two hours. Following evaporation in vacuo, the residue was mixed with water (50 ml) and ethyl acetate (15 ml) and stirred for several minutes. The resulting precipitate was collected by filtration and washed with water and ethyl acetate to afford 4-(5-acetylaminomethylfuran-2-yl)-2-thioureidothiazole (2.95 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:31])[C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(O)c1ccncc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccncc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and isonicotinic acid (66 mg, 0.54 mmol). The title compound was obtained as off-white powder (76 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH3:13])=[N:10][N:9]=2)=[CH:4][C:3]=1[N+:14]([O-])=O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:14][C:3]1[CH:4]=[C:5]([C:8]2[NH:12][C:11]([CH3:13])=[N:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1nnc(-c2ccc(Cl)c([N+](=O)[O-])c2)[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc(Cl)c(N)c2)[nH]1

Procedure:
The mixture consisting of 120 mg of 3-(4-chloro-3-nitrophenyl)-5-methyl-4H-[1,2,4]triazole, 30 ml of ethyl acetate and 644 mg of tin chloride was heated to reflux for 6 hours. After cooling, the mixture was washed with water, and the organic phase was dried over sodium sulfate and concentrated at 40° C. under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3ccc(Cl)cc3Cl)c2c2ccccc12
Yield: 13.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2,4-di-chloroaniline (105 mg, 0.65 mmol) to provide 204 (20 mg, 12% yield) as a white solid. LC-MS (M+H=356, obsd.=356).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[C:17]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35]2)=[CH:30][CH:29]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:38]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][C:28]([NH:27][C:17]([O:19][CH2:20][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:29][CH:30]=4)[CH:35]=3)(=[O:40])=[O:39])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: O=C(Nc1ccc2ccc(S(=O)(=O)Cl)cc2c1)OCc1ccccc1
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccc(NC(=O)OCc5ccccc5)cc4c3)C2=O)cs1

Procedure:
The title compound is prepared from 4-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)thiophene-2-carbonitrile hydrochloride as described in EXAMPLE 125, Part C using N-Cbz-7-aminonaphthalene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:23][CH2:24][CH2:25][CH2:26]I>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:26][CH2:25][CH2:24][F:23])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FCCCI
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(CCCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
18 g (81.72 mmol) of [(diphenylmethylene)amino]acetonitrile were initially charged in 500 ml of abs. THF, and 39.22 ml (98.06 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 15 min. Subsequently, the reaction solution was warmed up to 0° C. and 16.9 g (89.89 mmol) of 1-fluoro-3-iodopropane were added dropwise to the reaction solution, which was stirred at 0° C. for a further 15 min. The reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed with saturated aqueous sodium chloride solution. The aqueous phase was reextracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent: 100% toluene, post-purification with dichloromethane/cyclohexane=1/1 to 2/1). A total of 16.73 g of the target compound (73% of theory) were obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])/[CH2:18][CH2:19][CH2:20][C:21]2[C:26]/1=[CH:25][CH:24]=[CH:23][CH:22]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C1\CCCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (2.112 ml, 8.26 mmol) and ethyl(2E)-3,4-dihydronaphthalen-1(2H)-ylideneacetate (1.785 g, 8.26 mmol) in CH2Cl2 (33.3 ml) at 0° C. was added TFA (0.064 ml, 0.826 mmol) dropwise. Removed the ice bath and stirred at room temperature for 4 hours. Dilute with CH2Cl2 and wash twice with saturated NaHCO3. The organics were dried over sodium sulfate, concentrated, and purified on silica gel 20% EtOAc/Hex.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([OH:13])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:26]([NH:30][C:11](=[O:13])[CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)[CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)Cc1ccc2[nH]ccc2c1
Reactant: CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)Cc1ccc2[nH]ccc2c1
Yield: 77 %

Procedure:
A solution of indole-5-acetic acid (2.0 g), 4-dimethylaminopyridine (1.5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.4 g), and butylamine (1.2 ml) in methylene chloride was stirred under a nitrogen atmosphere for 18 hr. The reaction was diluted with methylene chloride, washed (10% (v/v) hydrochloric acid, water, brine), dried (MgSO4), and evaporated to give N-butylindole-5-acetamide (2.03 g, 77%) as an amber oil: NMR (300 MHz, CDCl3): 0.84(t, 3H, N(CH2)3CH3), 3.16(m, 2H, NCH2), 3.68(s, 2H, ArCH2), 5.44(br s, 1H, NH), 6.51(m, 1H, H2 -indole), 8.49(br s, 1H, NH).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8](=[N:16][OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:21][C:22]([NH2:24])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:16][O:17][CH2:21][C:22]([NH2:24])=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: ON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
Sodium hydride (0.5 g., 50% w/w suspension in mineral oil) was added gradually to a stirred solution of 4,4'-dichlorobenzophenone oxime (2.6 g.) in dry dimethylformamide (20 ml.) keeping the temperature below 30° C. After 30 minutes, chloroacetamide (0.9 g.) was added to the stirred solution keeping the temperature below 30° C. After 16 hours stirring at ambient temperature the mixture was poured into water (100 ml.) and the subsequent mixture extracted with ether. The combined extract was washed with water, dried (MgSO4) and evaporated. The residue (2.5 g.) was added to a column of dry chromatographic silica-gel [300 g., previously deactivated by addition of 10% w/w water and then equilibrated with 10% v/w of a mixture of toluene and acetone (10:1 v/w)]. The column was then eluted with the same mixture of toluene and acetone to give, after evaporation of solvent, a solid residue (1.5 g.). The solid was recrystallised from ethyl acetate/petrol giving di-(4-chlorophenyl)methyleneamino-oxyacetamide m.p. 141°-142° C. (1.1 g.) in 34% overall yield.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([Mg]Br)[CH2:31][CH:32]=[CH2:33]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1)[CH2:32][CH:31]=[CH2:30]
Reactant: C=CCC[Mg]Br
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(I)c2)NC(=O)OC(C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: C=CCCc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccc(OC)cc2)c1
Yield: 62 %

Procedure:
To a solution of (5)-tert-butyl 3-(3-iodophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (510 mg, 1.0 mmol), Pd(dppf)Cl2 (10 mol %) in THF (5 ml) was added but-3-enylmagnesium bromide (8 ml, 4 mmol, 0.5 M in THF). The solution was then heated at reflux overnight. The solution was cooled down and quenched with ammonia chloride (aq) and filtered through celite. The filtrate was extracted with EtOAc (2×25 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (20-40% EtOAc/hexanes) to provide the desired product (270 mg, 0.62 mmol), 62%. MS (m/z) 439 [M+H]+. Intermediate I-1A was used in the synthesis of Example 4.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:35]([CH3:37])[CH3:36]>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:35]([CH3:37])[CH3:36])[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)Br
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc21
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (34%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23](=[O:26])[CH:24]=[CH2:25])([CH3:21])([CH3:20])[CH3:19].N12CCN(CC1)CC2>>[C:18]([O:22][C:23](=[O:26])[C:24]([CH:16]([C:13]1[O:12][C:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:15][CH:14]=1)[OH:17])=[CH2:25])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OC(C)(C)C)C(O)c1ccc(C(=O)OCc2ccccc2)o1
Reaction time: 96 h

Procedure:
5-Formyl-2-furancarboxylic acid benzyl ester (0.2 g, 0.87 mmol), acrylic acid tert-butyl ester (0.52 mL), and 1,4-diazabicyclo[2.2.2]octane (20 mg, 0.18 mmol) were mixed, and the mixture was stirred for 4 days. Excess acrylic acid tert-butyl ester was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH2:11][OH:12])=[O:4].CN(C)C=O>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH:11]=[O:12])=[O:4]
Reactant: COC(=O)c1sc(N)nc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1sc(N)nc1C=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.9 %

Procedure:
To a solution of the compound (1.35 g) obtained in Step 3 in 1,4-dioxane (68 ml)/N,N-dimethylformamide (13 ml) was added manganese dioxide (3.68 g) at room temperature and the mixture was stirred at room temperature for 40 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.20 g).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12
Reactant: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CN1Cc2c(CCl)ncn2-c2ccccc2C1=O

Procedure:
6 g (24.6 mmol) of 4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one and 4.45 g of thionyl chloride are heated to boiling under reflux for 2 hours in 50 ml of benzene. The mixture is evaporated to dryness, the residue is taken up in chloroform and washed with 2 N sodium hydroxide. The organic phase is dried over magnesium sulphate and, after removal of the solvent, there is obtained 3-(chloromethyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 277°-280°.