Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Li+].C1(=O)O[CH2:27][CH2:26][O:25]1>CN(C)C=O.[I-].C[N+](C)(C)C>[CH3:15][C:13]1[N:14]=[C:7]2[C:6]([NH:5][CH2:4][C:3]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:2]=3[O:1][CH2:27][CH2:26][OH:25])=[CH:11][CH:10]=[CH:9][N:8]2[C:12]=1[CH3:16]
Reactant: O=C1OCCO1
Reactant: Cc1cccc(O)c1CNc1cccn2c(C)c(C)nc12
Agent: C[N+](C)(C)C
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCO)c1CNc1cccn2c(C)c(C)nc12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 41.2 %

Procedure:
To a solution of 8-(2-hydroxy-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.14 g, 0.5 mmol) in N,N-dimethylformamide (3 ml) was added lithium hydride (0.004 g, 0.51 mmol) and the mixture was stirred for 10 min at 100° C. Ethylene carbonate (0.055 g, 0.63 mmol) was added and the mixture was stirred for 10 min at 130° C. Tetramethylammonium iodide (0.054 g, 0.63 mmol) was added and the mixture was stirred for 12 h. at 140-145° C. The solvent was evaporated under reduced pressure and the residue was solved in methylene chloride, washed twice with saturated sodium bicarbonate. The organic layer was separated, dried and evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (100:6) as eluent to give 0.067 g (41%) of the title compound.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][C:41]([S:45]([CH3:47])=[O:46])=[CH:40][C:39]=4[F:48])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO.C1COCC1.C(Cl)Cl>[NH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:13]2[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:39]([F:48])=[CH:40][C:41]([S:45]([CH3:47])=[O:46])=[CH:42][C:43]=4[F:44])[N:32]=3)=[O:30])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)=O)cc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CS(=O)c1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (3.0 mg, 0.0044 mmol) was dissolved in MeOH (0.01 mL) and THF (0.05 mL), and 1.0 M aq. NaOH (0.017 mL, 0.017 mmol) was then added. The reaction mixture was stirred at room temperature for 60 min. The organic solvents and trace of water were removed under reduced pressure to give a crude intermediate. The residue was dissolved in DCM (0.04 mL), then TFA (0.044 mL, 0.58 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The solution was then concentrated again under reduced pressure. The residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give two mixtures of diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)) the diastereoisomers had the following properties:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[CH:24]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27][CH2:26][CH2:25]1.[O-]CC.[Na+]>C(O)C.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:32]=[C:30]([NH:29][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:31]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a mixture of 1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (1.57 g, 5.0 mmol) and N-cyclopentylguanidine hydrochloride (1.07 g, 6.6 mmol) in ethanol (50 mL) was added sodium ethoxide (2.5 mL, 21 wt % in ethanol, 6.6 mmol). The resulting suspension was stirred overnight at room temperature, then diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (7:3 to 3:2 hexanes-ethyl acetate) provided 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (1.77 g, 83%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.44 (d, 1 H), 8.05 (d, 1 H), 7.60 (d, 2 H), 7.28 (m, 1 H), 7.06–6.96 (m, 3 H), 6.38 (d, 1 H), 5.31 (broad, 1 H), 4.38 (m, 1 H), 3.88 (s, 3 H), 2.12 (m, 2 H), 1.84–1.53 (m, 6 H); MS m/z 420 (M+1).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9])(=O)C.C([O-])(O)=O.[Na+].[CH2:19](O)[CH3:20]>>[CH2:19]([O:10][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][N:13]=[C:5]([NH2:4])[CH:6]=1)[CH3:20]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccnc(N)c1
Yield: 79 %

Procedure:
2-Acetylamino-isonicotinic acid (10.8 g, 60.0 mmol) was suspended in ethanol (150 mL) and BF3OEt2 (22 mL, 138 mmol) was added. The mixture was refluxed overnight, and after cooling to room temperature 10% NaHCO3 (250 mL) was added. The product was extracted with chloroform and the combined organic extracts were washed with water and dried. Filtering and concentration afforded 2-amino-isonicotinic acid ethyl ester (7.46 g, 79%) as pale yellow crystals.
Reaction SMILES: C(C(CC=C)C[O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)C=C.C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>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.C1(C)C=CC=CC=1>[CH2:13]([Si:7]([CH2:12][CH:11]=[CH2:10])([OH:6])[C:8]1[CH:9]=[CH:10][C:11]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:12][CH:13]=1)[CH:8]=[CH2:9]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Reactant: COc1ccc(B(O)O)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: [K+]
Solvent: Cc1ccccc1
Product: C=CC[Si](O)(CC=C)c1ccc(-c2ccc(OC)cc2)cc1
Yield: 54 %

Procedure:
A mixture of the 4-(diallylhydroxysilyl)iodobenzene (151 mg, 0.46 mmol) obtained in Example 17, Pd(PPh3)4 (15.9 mg, 0.014 mmol), K2CO3 (94.8 mg, 0.69 mmol), and 4-methoxyphenyl boronic acid (83.4 mg, 0.55 mmol) was added with dist.toluene (5 mL). Subsequently, the resultant mixture was stirred under a nitrogen atmosphere at 80° C. for 38 hours to obtain a reaction mixture. Thereafter, a salt formed in the reaction mixture was removed by filtering with celite. The solvent was distilled from the organic layer with an evaporator to obtain a crude product. After that, the crude product thus obtained was separated and purified by silica gel column chromatography (hexane/EtOAc=3/1), and thereby 4-(diallylhydroxysilyl)-4′-methoxybiphenyl was obtained (76.1 mg, 54% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.O.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.C(O)C>[CH:10]1([CH2:9][NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])=[CH:23][CH:24]=3)[CH:3]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: Clc1cc(NCC2CC2)ncn1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cc(NCC3CC3)ncn2)cc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
In a microwave reaction vessel, slurry 6-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (560 mg, 3 mmol), [4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (1.1 g, 4 mmol), and tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.15 mmol) in toluene (4 mL). Add ethanol (1 mL) followed by potassium carbonate (0.9 g, 6 mmol) dissolved in water (300 □L). Irradiate in microwave (300 watts) at 120° C. for 60 min. Cool to room temperature, pour reaction mixture into 1N NaOH (250 mL) and extract with DCM (3×100 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 2:3 over 45 min; 40 mL/min) to obtain the desired intermediate (450 mg, 38%) as a yellow solid. MS (ES+) m/z: 355 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:23](Cl)(=[O:25])=[O:24])=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:4]([O:5][CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[C:3]=1[S:23]([NH:30][CH:27]1[CH2:29][CH2:28]1)(=[O:24])=[O:25]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2S(=O)(=O)Cl)CC1
Product: O=S(=O)(NC1CC1)c1c(OC2CCNCC2)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-1-carboxylate (0.70 g, 1.8 mmol) was dissolved in cyclopropylamine (8 ml) and stirred at room temperature for 30 min. The solution was concentrated in in vacuo and then azeotroped with toluene (4 times). The residue was redissolved in dichloromethane: trifluoroacetic acid/1:1 (20 ml) and stirred at room temperature for 15 min. The solution was concentrated in vacuo, then partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous was reextracted with ethyl acetate (4 times), and the combined organics dried over anhydrous potassium carbonate. Concentration in vacuo afforded the title compound as a white powder (0.70 g).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C@:5]1([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH3:22])[CH:2]=[CH2:3].NC1C=C2C(=CC=1)C[C@]1(C3C(=NC=CC=3)NC1=O)C2.Br[C:51]1[CH:52]=[C:53]2[C:74](=[CH:75][CH:76]=1)[CH2:73][C:55]1([C:63]3[C:58](=[N:59][CH:60]=[CH:61][CH:62]=3)[N:57]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:56]1=[O:72])[CH2:54]2.NC1C=CC=CC=1.C([O-])(=O)C.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:27]1[CH:28]=[C:23]([C@@:5]2([CH3:22])[N:4]([CH2:1]/[CH:2]=[CH:3]/[C:76]3[CH:75]=[C:74]4[C:53](=[CH:52][CH:51]=3)[CH2:54][C:55]3([C:63]5[C:58](=[N:59][CH:60]=[CH:61][CH:62]=5)[N:57]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:69])[CH3:70])[C:56]3=[O:72])[CH2:73]4)[C:13](=[O:14])[C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:6]2)[CH:24]=[C:25]([F:30])[CH:26]=1
Reactant: C=CCN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(Br)cc3C2)c2cccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(C/C=C/c2ccc3c(c2)CC2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)C12CCCC2

Procedure:
A suspension of tert-butyl (8R)-9-allyl-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylate described in Intermediate 3 (0.292 g, 0.694 mmol) and 5-bromo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one described in Intermediate 13 (309 mg, 0.694 mmol Palladium(II) acetate (46.8 mg, 0.208 mmol), sodium acetate (0.57 mg, 0.694 mmol), and tris-2 methoxy phenyl phosphine (122 mg, 0.347 mmol), in DMF (3 ml) was microwaved at 130° C. for 1 hour. The mixture was filtered through a plug of celite, washing with water and ethyl acetate. The layers were separated, then the aqueous layer was washed with 3×30 mL EtOAc. The combine organic layers were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The oily residue was purified on a 40 g redisep column, eluting with ethyl acetate:hexanes, 0:100 to 50:50. The desired fractions were concentrated in vacuo to yield the title compound. MS: m/z=785 (M+1).
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][N:6]1[C:5]2[CH:31]=[C:32]([F:33])[C:2]([F:1])=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]([C:18]1[N:19]=[C:20]([CH3:30])[S:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:17]
Reactant: CN(C)CCCl
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3n2CCN(C)C)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared from (RS)-1-[2-(5,6-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (300 mg) and (2-chloro-ethyl)-dimethyl-amine, according to a procedure similar to that described for Example 71 as a white solid (88 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[C:10](=[N:13]OC)[CH2:11][O:12][C:8]=2[CH:7]=1>C1COCC1>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[CH:10]([NH2:13])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: CON=C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Solvent: C1CCOC1
Product: NC1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
The mixture of 6-((2,4-dichlorobenzyl)oxy)-N-methoxy-1-benzofuran-3(2H)-imine (1.23 g) and THF (dry) (36 mL) was added dropwise to a solution of borane tetrahydrofuran complex solution (1.0 mol/L, 7.27 mL) at 0° C. The mixture was stirred at 60° C. overnight. After cooling, the mixture was quenched with water and 1N NaOH (15 mL). The mixture was stirred at 60° C. for 5 h. After cooling, the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The solid was dissolved in EtOAc and to the solution was added 4M HCl in EtOAc dropwise. The precipitate (850 mg) was collected by filtration. The solid was dissolved in 28% aqueous ammonia and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (721.3 mg).
Reaction SMILES: Br.Br[C:3]1[CH:15]=[N:14][C:6]2[NH:7][CH2:8][CH2:9][C:10](=[O:13])[NH:11][CH2:12][C:5]=2[CH:4]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[O:13]=[C:10]1[CH2:9][CH2:8][NH:7][C:6]2[N:14]=[CH:15][C:3](/[CH:18]=[CH:17]/[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][C:5]=2[CH2:12][NH:11]1
Reactant: O=C1CCNc2ncc(Br)cc2CN1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: Br
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CNC(=O)CCN2
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask was charged with 8-bromo-2,3,5,6-tetrahydropyrido[2,3-b][1,5]diazocin-4(1H)-one hydrobromide (0.5 g, 1.48 mmol), tert-butyl acrylate (1.1 mL, 7.42 mmol), and (i-Pr)2EtN (1.5 mL, 8.88 mmol) followed by 15 mL DMF. The solution was de-oxygenated with argon for 20 minutes. The mixture was treated with Pd(OAc)2 (17 mg, 0.07 mmol) and P(o-tol)3 (45 mg, 0.15 mmol) then heated to 100° C. for 18 hours (overnight). After cooling, the dark mixture was treated with activated charcoal (100 mg) and filtered through celite. The filtrate was partitioned between 150 mL CH2Cl2 and 50 mL H2O in a separatory funnel. The organic layer was separated and treated with 3×50 mL saturated sodium chloride solution then dried over MgSO4 and concentrated to give a brown residue. This residue was triturated with 20% Et2O:hexanes to give a solid. The solid was collected and subjected to flash chromatography on silica gel using 5% MeOH:95% CH2Cl2. Yield: 200 mg (44.5%); 1H-NMR (400 MHz, DMSO-d6) δ 8.12 (d, 1H, J=2.4 Hz), 7.74 (d, 1H, J=2.4 Hz), 7.44 (m, 1H), 7.41 (d, 1H, J=16.0 Hz), 6.94 (t, 1H, J=6.4 Hz), 6.29 (d, 1H, J=15.6 Hz), 4.46 (d, 2H, J=7.6 Hz), 3.61 (m, 2H), 2.73 (t, 2H, J=7.2 Hz), 1.46 (s, 9H); ESI MS m/z 304 [C16H21N3O3+H]+
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([O:16]C)=[O:15])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(=O)n(C2CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(=O)n(C2CCCCC2)c1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a solution of methyl 1-cyclohexyl-6-oxo-1,6-dihydropyridine-3-carboxylate (100 mg, 0.43 mmol) in 10 mL of THF:MeOH (3:1) was added 1M LiOH (1 mL, 1 mmol). The solution was stirred at room temperature until starting material was consumed as determined by LC-MS. The solution was then concentrated in vacuo, acidified with 2 N HCl to pH 2, and extracted with EtOAc (3×). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give 60 mg (63%) of the title compound as a golden yellow solid. MS m/z: 222.1(M+1).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:25]2[CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH:20]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:33]3[CH2:32][CH2:31][CH:30]([CH:20]4[C:19]5[CH:18]=[CH:17][CH:16]=[CH:15][C:25]=5[CH2:24][CH2:23][C:22]5[CH:26]=[CH:27][CH:28]=[CH:29][C:21]4=5)[CH2:35][CH2:34]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)CCc1ccccc1C2C1CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C2c3ccccc3CCc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 89% overall yield. FDMS m/e=466 (M+ of free base). α[D]589 =-10.02 (c=0.72, methanol).
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:18](OC)=[O:19])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:5]=[C:4]([CH:18]=[O:19])[CH:3]=1
Reactant: COC(=O)c1cc(Br)n(S(=O)(=O)c2ccc(OC)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)n2cc(C=O)cc2Br)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution (30 mL) of methyl 5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrole-3-carboxylate (3.00 g) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution (11.0 mL) of diisobutylaluminum hydride in toluene was added dropwise over 15 min, and the mixture was further stirred at −78° C. for 1 hr. A 1.5 mol/l solution (5.0 mL) of diisobutylaluminum hydride in toluene was added, and the mixture was stirred at −78° C. for 15 min, and at 25° C. for 2 hr. 1 mol/l Hydrochloric acid (40 mL) was added to the reaction mixture, and the mixture was stirred at 25° C. for 15 min and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (30 mL) of the residue in acetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate (281 mg), N-methylmorpholine N-oxide (1.41 g) and molecular sieves 4A powder (1.5 g) were added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a brown oil (yield 2.07 g, 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[N:20][NH:21][C:22](=[NH:24])[NH2:23])[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[F:19].N>CN1C(=O)CCC1.[Cu]I>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:21]([C:22](=[NH:24])[NH2:23])[N:20]=[C:9]2[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[F:19]
Reactant: N=C(N)NN=C(Cc1c(F)ccc(F)c1F)c1cc(Cl)ccc1Br
Agent: [Cu]I
Agent: N
Solvent: CN1CCCC1=O
Product: N=C(N)n1nc(Cc2c(F)ccc(F)c2F)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.23 h

Procedure:
4.60 g (10.96 mmol) of 2-[1-(2-bromo-5-chlorophenyl)-2-(2,3,6-trifluorophenyl)ethylidene]hydrazinecarboximidamide (the synthesis of this compound is described in WO 2010/065275, Example 3, Step B, page 36-37) and 2.09 g (10.96 mmol) of copper(I) iodide were initially charged in NMP (150 ml) in a 1 l round-bottom flask, and then stirred in an oil bath preheated to 170° C. for 14 minutes. The reaction mixture was subsequently cooled in an ice bath and admixed with an ice/water mixture (400 ml), and concentrated aqueous ammonia solution (200 ml) was added. After stirring for 15 minutes, the solids were filtered off with suction. The residue was dissolved in ethyl acetate, washed twice with water and dried, and the solvent was removed on a rotary evaporator. 3.00 g (39% of theory, 49% purity) of the title compound were obtained. The crude product was reacted further without purification.