Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH:14]=[O:15])[CH:3]=1
Reactant: Cc1cc(Nc2ncccc2CO)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2ncccc2C=O)no1
Temperature: 60 °C
Reaction time: 48 h
Yield: 101.5 %

Procedure:
3.3 g (16 mmol) of (2-(5-methyl-3-isoxazolyl)amino-3-pyridinyl)methanol was dissolved in chloroform (60 mL), and 4.3 g (49 mmol) of manganese dioxide was added thereto. The resulting mixture was stirred for 48 hours at 60° C. The reaction mixture was filtered, and the filtrate was concentrated. Thus, 3.3 g of the title compound was obtained as an orange-colored viscous product (yield: quantitative).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.C(OCC)(=O)C.[CH3:27][N:28](C=O)C>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>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:27]#[N:28])[CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(=O)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1cc(=O)oc2ccc(C#N)cc12
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
Trifluoro-methanesulfonic acid 4-methyl-2-oxo-2H-chromen-6-yl ester (10.38 mg, 33.7 mmol), Zn (CN)2 (4.7 g) and Pd(PPh3)4 (3.8 g) were dissolved in DMF (200 mL) at room temperature in a sealed tube. After 10 min, the reaction mixture was heated to 150° C. for 4 h. The reaction mixture was then cooled to room temperature and ethyl acetate (800 mL) was added. The reaction mixture was then poured into a separation funnel, washed with water (2×400 ml) and brine (2×600 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified on silica gel eluted with 30-80% ethyl acetate in hexanes to yield 4-methyl-2-oxo-2H-chromene-6-carbonitrile as a white powder.
Reaction SMILES: C([S@@](N)=O)(C)(C)C.[C:8]1([C@@H:14]([O:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[C@@H:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C@H:14]([O:28][S@:29]([C:31]([CH3:32])([CH3:34])[CH3:33])=[O:30])[C@H:15]([NH:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH3:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)[C@H](O[S@](=O)C(C)(C)C)c2ccccc2)cc1
Agent: CC(C)(C)[S@@](N)=O
Product: Cc1ccc(S(=O)(=O)N[C@H](C)[C@@H](O[S@@](=O)C(C)(C)C)c2ccccc2)cc1
Yield: 86 %

Procedure:
Preparation of (S)-t-butyl sulfinamide from (S)-2-Methyl-2-propylsulfinic acid (1R,2S)-1-phenyl-2-(4-toluenesulfonylamino)-propyl ester: The same procedure described above was followed, an furnished the title product in 86% yield and 96% ee. (HPLC, Chiralpak AS column, 90:10 hexane/ethanol; 1.2 mL/min, 222 nm; (R)-TBSA rt=6.6 min; (S)-TBSA, rt=9.4 min.). 1H NMR(CDCl3): δ 1.18 (s, 9H), 3.82 (br, s, 2H). 13C NMR (CDCl3): δ 22.1, 55.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH3:11][O:10][C:5]1[C:6]([CH2:7][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc(O)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(O)cc1CN1CCCC1
Yield: 87.2 %

Procedure:
5-Hydroxy-2-methoxybenzaldehyde (4.5 g, 0.03 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.1 mL, 0.037 mol) and NaB(OAc)3H (7.8 g, 0.037 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (50 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×50 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.42 g, 89%) was obtained as brown crystals. LCMS-data: (M+H)+ 208.1 and 209.1 (calculated for C12H17NO2 207.3). 1H NMR data (DMSO-d6): 8.79 (br. s, 1H ArOH), 6.81 (d, 1H, J=8.1 Hz, Ar—H), 6.74 (d, 1H, J=4.9 Hz, Ar—H); 6.64 (dd, 1H, J1=1.9, J2=8.1, Ar—H), 3.73 (s, 2H, OCH3), 3.42 (s, 2H, ArCH2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N), 1.59-1.73 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](Cl)=[C:7]([CH:15]=1)[O:8][C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11].[Cl:17]C1C=CC(O[C@@H](C)C(OC)=O)=CC=1C>>[Br:1][CH2:2][C:3]1[CH:15]=[C:7]([CH:6]=[CH:5][C:4]=1[Cl:17])[O:8][C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](C)Oc1cc(CBr)ccc1Cl
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(C)c1
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(CBr)c1

Procedure:
The title compound was prepared following the same general protocol as described for the synthesis of the (S)-methyl 2-(5-(bromomethyl)-2-chlorophenoxy)propanoate (Step 2, Example 55), using the (S)-methyl 2-(4-chloro-3-methylphenoxy)propanoate instead of the (S)-methyl 2-(2-chloro-5-methylphenoxy)propanoate.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].CN(C)CCN(C)C.C([Li])CCC.[I:27]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.O1CCCC1>[I:27][C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Agent: CN(C)CCN(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ncccc1I
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a mixture of 2,2-dimethyl-N-pyridin-2-yl-propionamide (3.0 g, 17 mmol) described in Manufacturing Example 39-1-1, N,N,N′,N′-tetramethylethylenediamine (6.3 mL, 42 mmol) and tetrahydrofuran (60 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 30 mL, 47 mmol) at −78° C., which was stirred overnight at 0° C. Iodine (6.8 g, 27 mmol) was added to the reaction mixture at −78° C., and stirred for 1.5 hours at 0° C. Water and saturated aqueous sodium thiosulfate solution were added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (2.9 g, 57%).
Reaction SMILES: [CH2:1](N=C=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].N(C1CC(C)(CN=C=O)CC(C)(C)C1)=C=O.C1(N=C=O)C=CC(N=C=O)=CC=1.C1C(CC2C=CC(N=C=O)=CC=2)=CC=C(N=C=O)C=1>>[NH:7]([CH:8]=[O:9])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: O=C=NCCCCCCN=C=O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Agent: O=C=Nc1ccc(N=C=O)cc1
Product: O=CNc1ccccc1

Procedure:
Particularly preferred isocyanates are hexamethylene diisocyanate; 1,12-dodecane diisocyanate; cyclobutane-1,3-diisocyanate; cyclohexane-1,3- and -1,4-diisocyanate and mixtures of these isomers; 1-isocyanato-3,3,5-trimethyl-5-isocyanatomethyl cyclohexane; hexahydro-1,3- and/or -1,4-phenylene diisocyanate; perhydro-2,4'- and/or -4,4'-diphenylmethane diisocyanate; 1,3- and 1,4-phenylene diisocyanate; 2,4- and 2,6-tolylene diisocyanate and mixtures of these isomers; diphenylmethane-2,4'- and/or -4,4'-diisocyanate; naphthylene-1,5-diisocyanate; triphenylmethane-4,4',4"-triisocyanate; and polyphenyl polymethylene polyisocyanates of the type obtained by phosgenation of aniline-formaldehyde condensates.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2=[O:16])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Br:17]Br>C(Cl)Cl>[Br:17][CH:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)[C:13]1=[O:16]
Reactant: BrBr
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CCC2
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(Br)CC2
Yield: 107.4 %

Procedure:
To a solution of 1.4 g (0.00585 mol) of 7-methanesulfonamido-1-tetralone in 20 mL of methylene chloride was added dropwise a solution of 0.94 g (0.0059 mol) of bromine in 5 mL of methylene chloride. The progress of the reaction was followed by thin layer chromatography (fl. silica gel/CH2Cl2). A few additional drops of the bromine solution were added to completely consume the starting material. The solution was evaporated to dryness to give 2.0 g of 2-bromo-7-methanesulfonamido-1-tetralone, mp 87°-92° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1>>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(N)nc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (28 mg, 34%), MS (ISP) m/z=332.4 [(M+H)+], mp 306° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine (71.5 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[CH:38][C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:39]=[CH:38][C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1ccc2[nH]c(=O)oc2c1)c1cc(Cl)ncn1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4ccc5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
99 mg (0.40 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.10 g (0.40 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3H-benzoxazol-2-one and 0.07 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. The mixture was diluted with acetonitrile/water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:32][O:33][CH2:34][CH2:35][C:36]([OH:38])=O.[Cl:39][C:40]1[CH:70]=[CH:69][C:43]([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[CH2:61][O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:42][CH:41]=1>CN(C=O)C.O>[Cl:39][C:40]1[CH:70]=[CH:69][C:43]([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([N:55]4[CH2:60][CH2:59][N:58]([C:36](=[O:38])[CH2:35][CH2:34][O:33][CH3:32])[CH2:57][CH2:56]4)[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[CH2:61][O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:42][CH:41]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: COCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
71 mg of TBTU (0.22 mmol), 0.19 ml of ethyldiisopropylamine and 0.023 ml of 3-methoxy-propionic acid (0.22 mmol) were dissolved in 6 ml DMF and stirred for one minute at rt under argon. Then 100 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.22 mmol) were added and the reaction mixture was stirred for 22 h at rt. The reaction mixture was then diluted with 30 ml water and extracted with ethylacetate (twice). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 121 mg of a light red solid (97%). MS (ISP) 537.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[S:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][CH:22]=[CH:21]2)(=[O:17])=[O:16].NC1C=C2C(=CC=1)C=NC=C2.Cl.Cl.N1(S(C2C=C3C(=CC=2)C=NC=C3)(=O)=O)CCNCC1>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)(=[O:16])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2cnccc2c1
Agent: Cl
Agent: Nc1ccc2cnccc2c1
Agent: O=S(=O)(c1ccc2cnccc2c1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cnccc3c2)CC1

Procedure:
0.5 mL of triethylamine and 0.5 g of tert-butoxycarbonylpiperazine were added with stirring at room temperature to a dichloromethane solution (100 mL) of 6-chlorosulfonylisoquinoline (Reference Compound 2) synthesized according to Reference Example 2 from 500 mg of 6-aminoisoquinoline (Reference Compound 1), and reacted for 6 hours. After the completion of reaction, the reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 150 mg of the compound of interest as a white crystal (23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:18][C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:38][O:37][C:22]1[CH:21]=[C:20]([N:14]2[CH2:15][CH2:16][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[S:18][C:12]=3[C:13]2=[O:17])[CH:25]=[CH:24][C:23]=1[O:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28]
Reactant: COc1cc(Br)ccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(-c2cc3c(s2)C(=O)NCC3)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(OS(=O)(=O)c4ccc(C)cc4)c(OC)c2)CC3)cc1
Reaction time: 16 h
Yield: 85.5 %

Procedure:
Combine 2-(4-methoxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (0.245 g, 0.943 mmol), toluene-4-sulfonic acid 4-bromo-2-methoxy-phenyl ester (0.404 g, 1.13 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (27.3 mg, 0.05 mmol), and Cs2CO3 (0.461 g, 1.41 mmol) in dioxane (25 mL). Purge the reaction vessel with nitrogen for 5 min, and then add Pd2(dba)3 (8.6 mg, 0.09 mmol). Reflux the reaction mixture and stir 16 h. Dilute with EtOAc (100 mL), wash with water (2×30 mL), dry with Na2SO4, filter and concentrate. Purify the crude material by chromatography, eluting with 30-50% EtOAc/hexanes to give 0.432 g (86%) of the title compound. LC-MS/ES m/z 536.0 [M+H]+.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=[O:24])[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:16])=[CH:6]1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[CH2:32][CH2:33][CH3:34]>C(#N)C>[CH2:31]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][C:15](=[O:16])[C:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=2)=[O:24])[CH2:23][CH2:22]1)[CH2:32][CH2:33][CH3:34]
Reactant: CC(C)n1cc(C(=O)C(=O)NC2CCNCC2)c2ccccc21
Reactant: CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(NC(=O)C(=O)c2cn(C(C)C)c3ccccc23)CC1
Temperature: 65 °C
Reaction time: 72 h
Yield: 28.8 %

Procedure:
The title compound was prepared according to general procedure E described in Scheme 2. 2-(1-Isopropyl-1H-indol-3-yl)-2-oxo-N-(piperidin-4-yl)acetamide hydrochloride (200 mg, 0.64 mmol) was treated with acetonitrile (3 mL), K2CO3 (265 mg, 1.91 mmol), and n-butyl bromide (175 mg, 1.28 mmol). The reaction mixture was stirred at 65° C. for 72 h and was then concentrated under reduced pressure. The crude material was purified on silica gel (Biotage, 2-10% MeOH/DCM, 30 min.) to provide the title compound as a pink solid (68 mg, 29% yield): 1H NMR (400 MHz, CDCl3): δ 9.11 (s, 1H), 8.43 (t, 1H), 7.56 (d, 1H), 7.43 (q, 1H), 7.35 (t, 2H), 4.71 (m, 1H), 3.90 (m, 1H), 3.03 (d, 2H), 2.48 (d, 2H), 2.31 (t, 2H), 2.05 (d, 2H), 1.80 (m, 2H), 1.61 (d+m, 8H), 1.34 (m, 2H), 0.94 (t, 3H);
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[CH2:12]([OH:14])[CH3:13]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6](=[NH:7])[O:14][CH2:12][CH3:13]
Reactant: CCO
Reactant: COc1ccccc1C#N
Agent: Cl
Product: CCOC(=N)c1ccccc1OC
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-methoxy-benzonitrile (760 mg, 5.708 mmol) in anhydrous ethanol (125 mL) cooled to 0° C. After 3.5 h, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 2-methoxy-benzimidate hydrochloride (865 mg, 70%). It was used without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.I[CH2:13][CH2:14][O:15][CH3:16]>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To a slurry of sodium hydride (0.932 g, 23.0 mmol) in DMF (30 mL) was added indole (2.52 g, 21 mmol) portionwise at 10-20° C. over 5 minutes. The reaction mixture was stirred at rt for 1.5 h, and 2-iodoethylmethylether (4.8 g, 26 mmol) in DMF (10 mL) was added over 5 minutes. The mixture was stirred at rt for 2 h, quenched with ice/water, and extracted with tert-butylmethylether. The organics were washed, dried, and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 1-(2-methoxy-ethyl)-1H-indole (3.40 g) as a yellowish liquid. MS (ISP): m/e 176.4 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13]1[CH:21]2[N:16]([CH2:17][CH2:18][C:19](=O)[CH2:20]2)[CH2:15][CH2:14]1>[OH-].[K+].O>[CH2:13]1[CH:21]2[N:16]([CH2:17][CH:18]=[C:19]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[NH:9][CH:8]=3)[CH2:20]2)[CH2:15][CH2:14]1
Reactant: O=C1CCN2CCCC2C1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Yield: 38.2 %

Procedure:
A mixture of 5-nitro-1H-indole (4.48 g, 27.6 mmol) and and 7-octahydroindolizinone (5.0 g, 35.9 mmol) in methanolic potassium hydroxide (10% potassium hydroxide in 50 mL of methanol) was heated to reflux for 3.5 hours. The reaction was diluted with water and the precipitate was collected by filtration. The filter cake was triturated with hot diethyl ether and filtered. The filter cake was recrystallized from methanol and dried to give 2.99 g of the title compound. (38.5%). Calculated for C16H17N3O2: Theory: C, 67.83; H, 6.05; N, 14.83. Found: C, 68.07; H, 6.27; N, 14.82. MS(FD) (m/e): 283.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1Oc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.9 %

Procedure:
AMR01073 To an ice cooled solution of 2-(4-chlorophenoxy)benzonitrile (AMR01071, 200 mg, 8.75 mmol) in dry THF (10 mL) was added a solution of LiAlH4 (THF 1M, 1.75 mL) under nitrogen. After stirring at room temperature for 3 h, the reaction mixture was cooled again and quenched with the minimum amount of saturated NH4Cl solution. The insoluble material was removed by filtration, and washed with DCM. The filtrate was dried (MgSO4) and the solvent evaporated to give 2-(4-chlorophenoxy)benzylamine (AMR01073, 203 mg, 100%) as an oil, which was used in the next step without further purification. AMR01076 Following the same procedure, from AMR01071 (1.5 g, 6.53 mmol) and LiAlH4 solution (THF 1M, 13 mL) in dry THF (30 mL), 2-(4-chlorophenoxy)benzylamine (AMR0106, 1.38 g, 90%) was obtained as an oil. Rf: 0.35 (DCM/MeOH 9:1) 1H NMR (270 MHz, CDCl3) δ 1.42 (2H, br s, NH2), 3.84 (2H, s, CH2), 6.84-6.90 (3H, m, ArH), 7.13 (1H, m, ArH), 7.21 (1H, dd, J=7.6, 2.0 Hz, ArH), 7.26 (2H, AA′BB′, ArH) and 7.38 (1H, td, J=7.4, 1.7 Hz, ArH). LC/MS (APCI) tr=1.40 min, m/z 236.38 (34), 234.36 (M++H, 100), 217.29 (M+—NH3, 35).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]([C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)([CH3:28])[C:26]#[N:27]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:34]=[C:29]([C:25]([CH3:28])([CH3:24])[C:26]#[N:27])[CH:30]=[N:31][CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)(C#N)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C(C)(C)C#N)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propionitrile (Stage 220.1.1) to give the title compound as a white solid. (HPLC: tR 2.36 min (Method A); M+H=438 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.78-8.76 (m, 1H), 8.73-8.71 (m, 1H), 8.18-8.14 (m, 1H), 8.12 (s, 1H), 8.05-8.01 (m, 1H), 7.93-7.90 (m, 1H), 7.62-7.60 (m, 1H), 3.88 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H), 1.80 (s, 3H), 1.79 (s, 3H))