Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:15]=[C:16]([NH:21][CH:22]([C:24]2[CH:25]=[C:26]([C:41](O)=[O:42])[CH:27]=[C:28]3[C:33]=2[O:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][C:29]3=[O:40])[CH3:23])[CH:17]=[C:18]([F:20])[CH:19]=1.[Si:44]([O:61][CH2:62][CH2:63][NH:64][CH3:65])([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[Si:44]([O:61][CH2:62][CH2:63][N:64]([CH3:65])[C:41]([C:26]1[CH:27]=[C:28]2[C:33](=[C:24]([CH:22]([NH:21][C:16]3[CH:17]=[C:18]([F:20])[CH:19]=[C:14]([F:13])[CH:15]=3)[CH3:23])[CH:25]=1)[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])=[O:42])([C:57]([CH3:59])([CH3:60])[CH3:58])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.71 mmol) was added in one portion to 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 0.35 mmol, enantiomer 1; [α]D20°: +115°, 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (221 mg, 0.71 mmol) and 2-hydroxy-pyridine N-oxide (78 mg, 0.71 mmol) dissolved in DCM (2 mL) under argon. The resulting solution was stirred at RT overnight. The solution was evaporated to dryness, water was added and product was extracted with DCM. The organic phase was washed with brine and dried over magnesium sulfate, the solvent was evaporated to afford N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-(3,5-difluorophenylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (94%) as a white solid. Mass Spectrum: M+H+ 726.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[C:12]2=[C:13]3[C:17](=[CH:18][CH:19]=[C:11]2[O:10][CH2:9][CH2:8][N:7]=1)[N:16]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:15]=[CH:14]3.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:5][CH:6]1[C:12]2=[C:13]3[C:17](=[CH:18][CH:19]=[C:11]2[O:10][CH2:9][CH2:8][NH:7]1)[N:16]([S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH:15]=[CH:14]3
Reactant: CC1=NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (73 mg, 0.43 mmol) was added to a solution of 1-[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]ethanone (Intermediate 23, 67 mg, 0.21 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (0.14 g, 0.85 mmol) and triphenylphosphine (112 mg, 0.430 mmol) in DCM (5 mL). The mixture was heated at 43° C. for 1 hour and additional 1,1′-azobis(N,N-dimethylformamide) (0.030 g, 0.17 mmol) was added and the mixture was heated at 43° C. for an additional 2 hours. The mixture was cooled to room temperature and TFA (2.5 mL) was added and the mixture was stirred for 1 hour and evaporated. The residue was partitioned between DCM and 1 M NaOH. The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using 5% MeOH in DCM as the eluent to give 75 mg of 1-methyl-8-(phenylsulfonyl)-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole. Acetic acid (132 mg, 2.20 mmol) was added to a solution of the 1-methyl-8-(phenylsulfonyl)-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole (75.0 mg, 0.22 mmol) in DCM (10 mL) and the mixture was allowed to stir for 10 minutes at room temperature before sodium triacetoxyborohydride (0.070 g, 0.33 mmol) was added all in one portion. The mixture was stirred for 30 minutes and transferred to a separation funnel and washed with 1 M NaOH and brine. The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (5:94:1) as the eluent to give the title compound (28 mg) as a white solid. MS m/z 343 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.S(OC)(O[CH3:25])(=O)=O.[OH-].[Na+]>C(C(C)=O)C.O>[CH3:25][O:20][CH3:9].[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2
Reactant: COS(=O)(=O)OC
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)=O
Product: COC
Reaction time: 1 h

Procedure:
Into a mixture of 1 g of estrone, 0.5 ml of dimethyl sulfate and 10 ml of methyl ethyl ketone, 5 ml of the 10% NaOH aqueous solution was added over a period of one hour. The reaction temperature was maintained at 15° - 20°C. The resulting mixture was stirred for 1 hour. 10 ml of water was added to the reaction mixture and methyl ethyl ketone was distilled off. The crystals which formed during the distillation were filtered from the cooled reaction mixture, washed with water and dried to obtain 1.037 g of the 100% purity methyl ether of estrone in a 98.6% yield.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH2:19][C:20]1[C:24]([C:25]#[N:26])=[C:23]([S:27][CH3:28])[NH:22][N:21]=1>O1CCCC1>[CH3:28][S:27][C:23]1[NH:22][N:21]=[C:20]([NH:19][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[C:24]=1[C:25]#[N:26]
Reactant: CSc1[nH]nc(N)c1C#N
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CSc1[nH]nc(NC=C2C(=O)Nc3ccccc32)c1C#N

Procedure:
The named compound is prepared by substituting 3-amino-5-methylsulfanyl-1H-pyrazole-4-carbonitrile for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2003 gms. of 3-amino-5-methylsulfanyl-1H-pyrazole-4-carbonitrile by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[C:11]1([S:17][C:18]2([C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=O)[CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>C(O)(C)(C)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:21]2([C:18]3([S:17][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:20][CH2:19]3)[CH2:10][O:9]2)=[CH:26][CH:27]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: Clc1ccc(CCC2(C3(Sc4ccccc4)CC3)CO2)cc1
Reaction time: 14 h
Yield: 81.4 %

Procedure:
21 ml (0.29 mol) o& dimethyl sulphide and 32.5 g (0.26 mol) of dimethyl sulphate are added to 40 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 30 g (0.095 mol) of 4-chlorophenylethyl 1-phenylmercapto-cyclopropyl ketone in 90 ml of tert.-butanol are first added dropwise to the reaction mixture with stirring and 29.2 g of potassium hydroxide powder are then introduced, while the temperature of the reaction mixture is held at 20 to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is removed under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water and concentrated by removing the solvent under reduced pressure after drying over sodium sulphate. In this manner, 25.6 g (82% of theory) of 2-(4-chlorophenylethyl)-2-(1-phenylmercapto-cyclopropyl)oxirane are obtained in the form of an oily product which is reacted further without additional purification. ##STR68##
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[OH:29].[Na+].C(OO)(C)(C)C>ClCCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:29])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: O=C([O-])O
Agent: CC(C)(C)OO
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Yield: 114.2 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone (100 mg, 0.25 mmol, 1.0 equiv; Example 24) in anhydrous 1,2-dichloroethane (2 mL) was added sodium hydrogen carbonate (11 mg, 0.125 mmol, 0.5 equiv; [CAS RN 144-55-8]), tert-butyl hydroperoxide (189 mg, 227 μL, 1.25 mmol, 5.0 equiv, 5.5 M solution in decane; [CAS RN 75-91-2], TBHP) and dirhodium caprolactamate (1.7 mg, 0.0025 mmol, 0.01 equiv; [CAS RN 138984-26-6]; prepared according to M. P. Doyle, L. J. Westrum, W. N. E. Wolthuis, M. M. See, W. P. Boone, V. Bagheri, M. M. Pearson, J. Am. Chem. Soc. 1993, 115, 958-964). The reaction mixture was stirred at rt over night. Removal of the solvent mixture under reduced pressure and purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate followed by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 59 mg (57%) of the title compound as a white solid. MS (ISP): 413.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[S:24]1[CH2:28][CH2:27][S:26][CH:25]1[CH2:29][NH2:30].CCN(C(C)C)C(C)C>C(O)CCC>[S:24]1[CH2:28][CH2:27][S:26][CH:25]1[CH2:29][NH:30][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCC1SCCS1
Reactant: Oc1ccc(-c2oc3ncnc(Cl)c3c2-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Oc1ccc(-c2oc3ncnc(NCC4SCCS4)c3c2-c2ccccc2)cc1

Procedure:
This compound was prepared by a method analogous to that for 70. Briefly, compound 79 was heated with C-[1,3]dithiolan-2-yl-methylamine and DIEA in 1-butanol to provide the title compound. MS: 422.1 (M+1). 1HNMR (DMSO-d6) ppm 9.86 (s, 1H), 8.33 (s, 1H), 7.59-7.51 (m, 5H), 7.26 (d, 2H, 7.00 Hz), 6.74 (d, 2H, 7.00 Hz), 5.35 (t, 1H), 4.69 (t, 1H, J=6.00 Hz), 3.64 (t, 2H, J=6.00 Hz), 3.13-3.05 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][CH2:13][C:14](OCC)(OCC)OCC>COCCOCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:12][CH2:13][C:14]1[O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[N:1]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CCOC(CCl)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1cccc2oc(CCl)nc12
Temperature: 25 °C
Yield: 17.9 %

Procedure:
To a RT solution of 2-amino-3-nitrophenol (14.7 g, 95 mmol, 1.0 equiv) in 2-methoxyethylether (136 mL) was added 2-chloro-1,1,1-triethoxyethane (19.1 g, 97.3 mmol, 1.02 equiv) and p-toluene sulfonic acid hydrate (25 mg, 0.13 mmol, 0.2 equiv). The resulting mixture was heated to reflux overnight. After the reaction was cooled to RT, the solvent was removed in vacuo. The solid was suspended in methanol (40 mL), stirred and filtered to provide the desired product as a red solid (3.61 g). The filtrate provided an additional 9.8 g of the title compound through an additional methanol treatment (13.4 g, 98% combined).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:14])[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:14])[C:6]([S:9]([CH3:12])(=[O:10])=[O:11])([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)(C)S(C)(=O)=O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)(C)S(C)(=O)=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
[2-Methanesulfonyl-2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (700 mg, 1.22 mmol) and (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (565 mg, 1.26 mmol) in 3:1 DME/H2O (15 mL) were treated with Pd(PPh3)4 (56 mg, 0.0050 mmol) and NaHCO3 (350 mg, 4.15 mmol). The mixture was stirred in a sealed tube at 80° C. for 24 hours. The mixture was filtered through a fitted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford (2-methanesulfonyl-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (150 mg, 15%) as a white solid (TFA salt): 1H NMR (CD3OD, 300 MHz) 7.85 (m, 10H), 5.25 (m, 2H), 4.24 (d, J=7.5 Hz, 1H), 4.13 (m, 2H), 3.88 (app d, J=7.5 Hz, 2H), 3.71 (s, 3H), 3.66 (s, 3H), 2.99 (s, 3H), 2.57 (m, 2H), 2.16 (m, 10H), 1.81 (s, 3H), 1.79 (s, 1H), 0.93 (m, 6H); MS (ESI) m/z 818 [M+H]+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](SC)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:30][CH2:29][O:28][CH2:27]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([N:31]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:37][CH:36]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)c1
Temperature: 250 °C
Yield: 19.7 %

Procedure:
The title compound was prepared in the following manner from N-tert-Butyl-3-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (0.1 g, 0.3 mmol), 4-(4-morpholino)aniline (90 mg, 0.5 mmol), N,N-Diisopropylethylamine (0.124 mL, 0.712 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were heated in the microwave at 250° C. for 30 minutes. An LCMS showed product and left over amine. The reaction was concentrated and redissolved in 3 ml of DMSO and placed onto the Gilson. The most pure fractions were combined basified with sat. sodium bicarbonate and extracted with DCM, dried filtered and concentrated to give N-tert-Butyl-3-[2-(4-morpholin-4-yl-phenylamino)-pyrrolo-[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a yellow solid (30 mg, 20%). MP 225-226 C. LCMS (E/I+) 507 (M+H). NMR 1H (DMSO-d6)-9.40 (bs, 1H), 8.96 (bs, 1H), 8.52 (bs, 1H), 7.77 (d, 1H, J=7.40 Hz), 7.50-7.45 (m, 2H), 7.22-7.05 (m, 4H), 6.93 (s, 2H), 6.54 (d, 1H, J=7.91 Hz), 4.45-4.40 (m, 1H), 3.18-3.25 (m, 2H), 3.04-3.11 (m, 2H), 1.98-2.06 (m, 2H), 1.74-1.84 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 100 °C
Yield: 80.2 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200.0 mg, 0.518), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine-1(2H)-carboxylate (160.1 mg, 0.518 mmol), tetrakis(triphenylphosphine)palladium (119.7 mg, 0.104 mmol), Na2CO3 (1.30 ml, 2.59 mmol) and DME (50 mL). The reaction mixture was stirred under nitrogen at 100° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (183.4 mg, 80%). LRMS (APCI pos): m/e 442 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.41 (d, 1H), 7.36 (s, 1H), 7.03 (t, 1H), 6.54 (dd, 1H), 6.47 (m, 2H), 6.30 (m, 1H), 4.13 (m, 2H), 3.83 (br s, 2H), 3.68 (m, 2H), 2.64 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([Cl:9])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5]1.Cl.[CH2:23]=O.N>CO.O>[Cl:9][C:8]1[N:4]2[CH2:3][CH2:2][NH:1][CH2:23][C:5]2=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: COC(=O)c1cn(CCN)c(Cl)c1-c1cccc(C#N)c1
Reactant: C=O
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2cccc(C#N)c2)c(Cl)n2c1CNCC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 224.9 %

Procedure:
To a solution of 8.41 g (27.7 mmol) of methyl 1-(2-amino-ethyl)-5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in 20 ml of methanol are added 84 ml (340 mmol) of aqueous 4N hydrochloric acid solution. The formation of a white precipitate is rapidly observed and the medium then becomes clear, while the mixture is heated to 90° C. and 0.92 g (10 mmol) of paraformaldehyde is added. Heating is continued at 90° C. for 4 hours. After cooling, the reaction medium is poured into 200 ml of water and the solution is basified by adding aqueous ammonia. The product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give an orange-coloured oil, which is chromatographed on a column of 80 g of silica gel, eluting with a mixture of 2% methanol in dichloromethane, to give 7.1 g of methyl 6-chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate in the form of a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].C(O)(=O)C>COCCOC>[CH:16]([CH:10]([CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (2.338 g, 58.5 mmol) in DME (20 mL) was added dropwise a solution of ethyl 3-phenylpropanoate (3.2 g, 19.49 mmol) and ethyl formate (6.28 mL, 78 mmol) in DME (20 mL) at room temperature. The reaction mixture was then stirred overnight. It was neutralized with acetic acid (4 mL), then extracted with EtOAc. The organic phase was collected, washed with brine, dried over Na2SO4, filtered, and concentrated affording the crude title compound (4.02 g, 100% yield). LCMS: rt=2.82 and 3.51 min (a mixture of ketone and enol isomer), [M+H+]=207.1
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:35](=[CH:36][CH:37]=2)[O:34][C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]5[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[O:19])[CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:38])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:39][C:40](OC(C)=O)=[O:41].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:35](=[CH:36][CH:37]=2)[O:34][C:12]2([CH2:13][CH2:14][N:15]([C:18]([C:20]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]5[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[O:19])[CH2:16][CH2:17]2)[CH2:11][C:10]3=[O:38])[CH2:2][CH2:3]1)(=[O:41])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N4CCNCC4)ccc2O3)nc2c(OC)cccc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N4CCN(C(C)=O)CC4)ccc2O3)nc2c(OC)cccc12
Reaction time: 4 h

Procedure:
To a solution of 165 mg of 6-(piperazin-1-yl)-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one in 2 mL of CHCl3 was added 0.165 mL of Ac2O and 0.33 ml of triethylamine and the mixture was stirred for 4 hrs. The mixture was partitioned between CHCl3 and 1N NaOHaq, and the organic layer was separated, washed with brine, dried over MgSO4, and concentrated. The residue was purified on preparative TLC (SiO2, CHCl3/MeOH=9/1) to afford the intended compound as a yellow powder. 1H-NMR (400 MHz, CDCl3) δ7.74 (1H, d, J=8.4 Hz), 7.45 (1H, ddd, J=8.4, 8.0, 0.8 Hz), 7.32-7.34 (1H, m), 7.18 (1H, dd, J=8.8, 1.4 Hz), 7.16 (1H, s), 7.06 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=8.8 Hz), 4.50-4.60 (1H, m), 4.00-4.20 (1H, m), 4.06 (3H, s), 4.02 (3H, s), 3.70-3.80 (2H, m), 3.50-3.70 (3H, m), 3.33-3.40 (1H, m), 3.00-3.20 (4H, m), 2.78 (1H, d, J=16.8 Hz), 2.72 (1H, d, J=16.8 Hz), 2.21-2.30 (1H, m), 2.10-2.20 (1H, m), 1.70-2.95 (2H, m). MS [M+H]+=559.