Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:15](=[O:16])[C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][N:7]3[CH:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23.Cl>O>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:15](=[O:16])[C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:7]3[CH:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23
Reactant: CCOC(=O)c1cn2c3c(c(Br)c(F)cc3c1=O)OCC2C
Agent: Cl
Solvent: O
Product: CC1COc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 17 h
Yield: 76.9 %

Procedure:
A mixture of ethyl 10-bromo-9-fluoro-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate (0.2 g, 0.54 mmol) and a 3N hydrochloric acid solution (15 ml) were heated at 100° C. with stirring for 17 hours. The reaction mixture was diluted twofold with water and filtered. The white solid, which was collected, was washed with water, triturated with acetone, and filtered. Drying in vacuo afforded a white powder (142 mg, 77% yield): m.p. >250° C. NMR (5% DMSO-d6/CF3CO2D, 250 MHz): 9.12 (s, 1H), 7.80 (d, 1H, J=8 Hz), 5.10-5.00 (m, 1 H), 4.80-4.70 (m, 1H), 4.60-4.50 (m, 1H), 1.52 (d,3H, J=7 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33](Br)[CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:32]=[C:33]([C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:16])[F:17])=[CH:13][C:8]=2[CH2:7][N:3]([C:4](=[O:6])[CH3:5])[CH2:1][CH3:2])[CH:34]=[C:35]([Cl:37])[CH:36]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(C)=O
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: N-ethyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-acetamide and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[F:1][C:2]([F:6])([CH3:5])[CH2:3][O:4][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CC(F)(F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(C)(F)F)cc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of 2,2-difluoropropanol (0.50 g, 5.20 mmol) in dichloromethane (52.0 mL) and triethylamine (0.50 g, 0.73 mL, 5.20 mmol) at 0° C. is added p-toluenesulfonyl chloride (0.99 g, 5.20 mmol). The mixture is allowed to slowly warm to room temperature over 24 h. The mixture is concentrated and is partitioned between diethyl ether and water. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The material is purified over silica gel to obtain 1.0 g of the title compound as clear crystals. MS (m/z) 250 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[NH:13]2)[CH:5]=[CH:6][CH:7]=1.ClC1C(F)=C(OC(=O)NC[C@@H]2C[C@@H]3[C@@H](C3)N2C(=O)NC2C3C(=CC=CC=3)N(C(=O)N)C=2)C=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:87]([C:90]1[C:98]2[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=2)[N:92]([CH2:99][C:100](O)=[O:101])[CH:91]=1)(=[O:89])[CH3:88]>C1COCC1>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[N:13]2[C:100](=[O:101])[CH2:99][N:92]2[C:93]3[C:98](=[CH:97][CH:96]=[CH:95][CH:94]=3)[C:90]([C:87](=[O:89])[CH3:88])=[CH:91]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC[C@@H]1C[C@H]2C[C@H]2N1)Oc1cccc(Cl)c1F
Reactant: CC(=O)c1cn(CC(=O)O)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)n1cc(NC(=O)N2[C@H](CNC(=O)Oc3cccc(Cl)c3F)C[C@H]3C[C@H]32)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)c1cn(CC(=O)N2[C@H](CNC(=O)Oc3cccc(Cl)c3F)C[C@H]3C[C@H]32)c2ccccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of [(1R,3S,5R)-1-(2-aza-bicyclo[3.1.0]hex-3-yl)methyl]-carbamic acid 3-chloro-2-fluoro-phenyl ester, trifluoroacetate (prepared as described in Example 115) (60.0 mg, 0.211 mmol) in THF (3 mL) was added HBTU (120 mg, 0.316 mmol), DIPEA (0.147 mL, 0.843 mmol) and (3-acetyl-indol-1-yl)-acetic acid (50 mg, 0.232 mmol). The reaction mixture was stirred at RT for 60 h. Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give after lyophilization of the purified HPLC fractions the title compound. MS (LC/MS): 484.0 [M+H]+; tR (HPLC conditions k): 3.69 min.
Reaction SMILES: [CH:1]1([N:4]([CH2:38][CH2:39]O)[C:5]([C:7]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]3([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)=[O:6])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:39][CH2:38][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1CC1
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (355) (120 mg, 0.22 mmol) and diisopropyl azodicarboxylate (0.22 mL, 1.12 mmol) in dichloromethane (30 mL) was added triphenyl phosphine (351 mg, 1.34 mmol) at room temperature and the reaction mixture was stirred for 15 min at the same temperature. The yellow color disappeared (silica TLC 5% methanol in ethyl acetate, Rf=0.2). The dichloromethane was removed in vacuo and the crude mass was purified by silica gel (normal, 100-200 mesh) column chromatography using a gradient eluent mixture of 1% to 5% methanol in dichloromethane to get pure 9-benzyloxy-2-cyclopropyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (356) (106 mg, 92%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[F:15])=[O:4]>CCOC(C)=O.[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]([F:15])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:16])[F:17])[CH:11]=1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(NC(=O)C(F)(F)F)c1

Procedure:
The crude acetamide was dissolved in EtOAc (50 mL), shacked with 10% Pd/C (450 mg) under H2 (50 psi) for 3 h. Filtration gave an N-(5-amino-2-fluoro-phenyl)-2,2,2-trifluoro-acetamide (8.42 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C@@H:7]([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:2].[BH4-].[Na+].O.Cl>CO.C(OCC)(=O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C@@H:7]([CH3:15])[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9]
Reactant: C[C@H](Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@H](Oc1cccc(CO)c1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of 1.48 g of tert-butyl(2S)-2-(3-formylphenoxy)propanoate in methanol (30 mL) was added 0.48 g of sodium borohydride under ice-cooling, followed by stirring for 1 hour. The reaction solution was diluted with ethyl acetate, added with water, neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.38 g of tert-butyl(2S)-2-[3-(hydroxymethyl)phenoxy]propanoate as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][O:11][CH3:12])[C:5]([CH3:7])=[O:6].C1(C)C=CC=CC=1.[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>C(OC(C)C)(C)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[N:8][O:9][CH2:10][O:11][CH3:12])[C:5]([CH:7]=[CH:21][N:22]([CH3:24])[CH3:23])=[O:6]
Reactant: COC(OC)N(C)C
Reactant: COCON=C(C(C)=O)C(=O)OC
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: COCON=C(C(=O)C=CN(C)C)C(=O)OC

Procedure:
6.4 g of 2-(methoxymethoxyimino)acetoacetic acid methyl ester in 30 of toluene are heated with 9 ml of N,N-dimethylformamidedimethylacetal for 5 hours at boiling. After cooling, the semi-crystalline residue is dissolved by heating in diisopropylether, the mixture is filtered. The precipitate obtained after cooling is filtered and dried to obtain the heading compound, m.p. 99°-100°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH2:12][Mg+].[Br-].B(F)(F)F.CCOCC>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]1([NH2:5])[CH2:12][CH2:11]1
Reactant: CC[Mg+]
Reactant: N#Cc1cc(Cl)ccc1Br
Agent: FB(F)F
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1(c2cc(Cl)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a stirred solution of 2-bromo-5-chlorobenzonitrile (10 g, 46 mmol) and Ti(Oi-Pr)4 (16.64 mL, 55 mmol) in THF (200 mL) at −78° C. was added EtMgBr (138 mL, 138 mmol) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. BF3-Et2O (17.2 mL) was added, and the solution was stirred for another 16 hours before it was quenched with aq. HCl solution and washed with EtOAc. The aqueous phase was adjusted to pH˜10 with aq. NaOH solution, and exacted with EtOAc (3×). The combined organic layers were concentrated to give a crude product which was purified by chromatography to afford title compound (2 g, yield 17.6%). MS: 246.7 (M+H+, 1C1) as oil.
Reaction SMILES: ClN1C(=O)CCC1=O.[I-:9].[Na+].[CH3:11][O:12][C:13]([C:15]1[NH:19][C:18]2[C:20]([Br:23])=[CH:21][S:22][C:17]=2[CH:16]=1)=[O:14].[O-]S([O-])=O.[Na+].[Na+]>CC(C)=O>[CH3:11][O:12][C:13]([C:15]1[NH:19][C:18]2[C:20]([Br:23])=[CH:21][S:22][C:17]=2[C:16]=1[I:9])=[O:14]
Reactant: [I-]
Reactant: COC(=O)c1cc2scc(Br)c2[nH]1
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1[nH]c2c(Br)csc2c1I
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of N-chlorosuccinimide (12 mmol) in acetone (25 mL) was added dropwise a solution of sodium iodide (12 mmol) in acetone (80 mL). 3-Bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester (10 mmol) in acetone (80 mL) was then added portionwise into the reaction mixture. After 1 hr of stirring, the reaction was poured into a solution of Na2SO3 10% and extracted with AcOEt. Organic phases were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography to give compound 69 as a yellowish solid in 68% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 3.96 (s, 3H), 7.26 (s, 1H), 9.22 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:34]=[O:35]>O1CCCC1>[OH:1][C:2]1[C:3]([C:11]2([CH2:34][OH:35])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ncccc21
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ncccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
To a solution of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (1.60 g, 4.70 mmol) in anhydrous tetrahydrofuran (30.0 mL) was added a solution of pre-prepared lithium diisopropylamide (10.3 mmol) in anhydrous tetrahydrofuran (30.0 mL) at −78° C. The reaction mixture was stirred at −78° C. for 0.5 h followed by the addiotion of para-formaldehyde (0.85 g, 28.2 mmol) in one portion. The reaction was stirred at −78° C. for 2 h and quenched with saturated ammonium chloride (20.0 mL). After the organic solvent was removed under reduced pressure, the residue was diluted with ethyl acetate (50.0 mL). The organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (1.95 g, 100%): 1H NMR (300 MHz, CDCl3) δ 8.22 (dd, 1H), 7.22-7.12 (m, 2H), 6.51 (s, 1H), 6.06 (s, 1H), 5.83 (d, 2H), 4.89 (s, 2H), 3.83-3.61 (m, 2H), 1.75-1.61 (m, 2H), 1.39-1.29 (m, 4H), 0.89 (t, 3H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=1[CH2:29][CH3:30]>C1COCC1>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[C:9]([CH2:29][CH3:30])[CH:10]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26][CH:25]=1)#[N:28]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(N)c(CC)c1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(NC(=O)NC(C)C)c(CC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of isopropyl isocyanate (130 mg, 1.55 mmol) in THF (2 ml) was added to a solution of the ethyl (RS)-(4-amino-3-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (500 mg, 1.55 mmol) described in Example 186.1 in THF (10 ml). The mixture was stirred overnight at room temperature. Thereafter, further isopropyl isocyanate (260 mg, 3.1 mmol) was added and the mixture was stirred overnight at 50° C. The reaction mixture was concentrated. The residue was suspended in CH2Cl2/MeOH (98:2) and the colorless solid was filtered off. The solid was washed with EtOH and dried under a high vacuum. Ethyl (RS)-(4-cyano-phenylamino)-[3-ethyl-4-(3-isopropylureido)-phenyl]-acetate (395 mg, 62%) was obtained as a colorless solid; MS: 409 ([M+H]+)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:8]=2[CH2:7][C:6]1=[O:18].Cl.[CH3:20][NH:21][CH3:22].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH3:20][N:21]([CH3:22])[CH2:2][CH2:3][CH2:4][N:5]1[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:8]=2[CH2:7][C:6]1=[O:18]
Reactant: COc1ccc2c(c1)CC(=O)N(CCCCl)C=C2
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: COc1ccc2c(c1)CC(=O)N(CCCN(C)C)C=C2

Procedure:
Into a 1-neck round-bottom flask was added 3-(3-chloro-propyl)-8-methoxy-1,3-dihydro-benzo[d]azepin-2-one (2.5 g, 0.0094 mol), dimethylamine hydrochloride (1.534 g, 0.01882 mol), Potassium iodide (0.468 g, 0.00282 mol), and Potassium carbonate (5.201 g, 0.03763 mol), in Acetonitrile (25 mL), and the reaction was stirred over night at 50° C. The reaction mixture was next partitioned between water and dichloromethane, and the layers were separated. The aqueous phase was extracted once with dichloromethane and the combined organic extract was washed with water. The organic solution was next extracted twice with 100 mL HCl solution (˜4N), and the aqueous extract was washed once with dichloromethane (50 mL). The aqueous solution of the chlorohydrate thus obtained was basified with solid Na2CO3 to pH 11. Extraction with dichloromethane, drying of the extracts (MgSO4), concentration and high vacuum drying provided 3-(3-dimethylamino-propyl)-8-methoxy-1,3-dihydro-benzo[d]azepin-2-one, which was used without further purification (oil, 1.13 g, 44%). LC/MS (ESI+) 275 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1.[CH3:17][Si](C)(C)[N-][Si](C)(C)C.[Na+].IC>C1COCC1>[CH3:17][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: c1cncc(-c2noc(-c3ccc[nH]3)n2)c1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cccc1-c1nc(-c2cccnc2)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-{5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl}-pyridine (1 g; 0.5 mmol) in 15 ml of dry THF at −70° C. was added 0.18 g of sodium hexamethyl disilazide (1 mmol), the reaction mixture was stirred at −70° C. for 30 min. and at 0° C. for 1 hour. The reaction mixture was cooled to −70° C. and added 0.076 g of iodomethane (0.52 mmol). The reaction mixture was stirred at −70° C. for ½ hour, then at room temperature overnight. The product was isolated by column chromatography. Yield 0.04 g of yellow solid (37%). Mp. 108-109° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:12]Br.C(O)(=O)C>C(Cl)(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=2[CH:11]=1
Reactant: CSc1nc2ccccc2s1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CSc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To the solution of 2-(methylthio)-1,3-benzothiazole (5.00 g, 27.58 mmol) in CHCl3 (85 mL) in a NaCl-ice water bath, bromine (4.24 mL, 82.8 mmol) was slowly added dropwise, followed by acetic acid (30 mL). The mixture was stirred at rt overnight. The white solid was filtered and then dissolved in EtOAc (200 mL). Saturated, aqueous Na2CO3 (200 mL) was added and the organic layer was separated, dried over MgSO4 and concentrated to dryness. Desired product (5.0 g, 70%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ8.30 (s, 1H), 7.76 (d, 1H), 7.59 (d, 1H), 2.79 (s, 3H); LC-MS m/z [M+H]+ 260.2 & 262.1, RT 3.65 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[C:6]2C(O)=O)#[N:2].O>CN1C(=O)CCC1>[F:15][C:12]([F:13])([F:14])[C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)c(C(=O)O)c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 135 °C
Reaction time: 0.67 h
Yield: 82.2 %

Procedure:
5-cyano-2-(trifluoromethyl)-1H-indole-3-carboxylic acid (Intermediate 36 2.09 g) was dissolved in NMP (10 mL) and H2O (1 mL) was then added. The mixture was heated to 130-140° C. overnight under nitrogen. The solution was cooled to room temperature and H2O (30 mL) was added and the solution stirred for 40 min. and then filtered. The cake was washed with H2O. The product is then dried under vacuum at 40° C. to give the title compound (1.42 g);
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1>CO.[C].[Pd]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1
Reactant: CC(=O)NCC=C1CCc2ccc3nn(C)cc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3nn(C)cc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of N-[2-(2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethyl]acetamide (311 mg, 1.22 mmol) in methanol (12 mL) was added palladium-carbon powder (31 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (methanol/ethyl acetate=0/100→25/75) to give the title compound (229 mg, yield 73%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[C:7]([O:31]C)=[C:8]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:9][N:10]([CH2:21][CH:22](OC)OC)S(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[F:30][C:28]1[CH:29]=[C:6]([F:5])[C:7]([OH:31])=[C:8]2[C:27]=1[CH:22]=[CH:21][N:10]=[CH:9]2
Reactant: COc1c(F)cc(F)cc1CN(CC(OC)OC)S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1c(F)cc(F)c2ccncc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of aluminiumchlorid (3.85 g, 28.9 mmol, 5 eq.) in DCM (40 mL), N-(3,5-difluoro-2-methoxy-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzenesulfonamide (2.40 g, 5.78 mmol, 1 eq.) in DCM (15 mL) was added dropwise at r.t. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was poured on ice (300 g). The mixture was extracted with DCM (3×200 mL). The comb. org. phases were washed with sat. aq. NaHCO3 soln. (150 mL) and sat. aq. NaCl soln. (1×100 mL). The resulting suspension was filtered and the solid was rinsed with DCM (20 mL). The solid was dried at h.v. to give the title compound as a yellow solid. The product was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2c(c1)c1ccccc1n2C

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 9-methyl-9H-carbazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 429.05 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:30](Br)[CH2:31][Br:32].O>CN(C=O)C>[Br:32][CH2:31][CH2:30][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@:10]2([CH2:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:11]1=[O:19]
Reactant: BrCCBr
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(CCBr)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 40.6 %

Procedure:
To a solution of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (173 mg, 0.64 m mol) in DMF (2 mL) was added KHMDS (0.5 M, 1.4 mL) dropwise at room temperature. The mixture was stirred for half an hour before adding ethylene dibromide (300 mg, 1.6 mmol). The mixture was warmed to 50° C. and stirred at that temperature for 14 hours. The mixture was poured into water, extracted with ethyl acetate (3×15 mL), dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 5-10% ethyl acetate in petroleum ether) to give the title compound as white solid (98 mg, 41%). LC/MS m/e calcd. for C18H15BrClNO: 375, observed (M+H)+: 376.