Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[O:11][CH2:12][O:13][CH3:14].C([O-])(=O)C.[K+].[B:20]1(B2OCC(C)(C)CO2)[O:25]CC(C)(C)C[O:21]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][O:13][CH2:12][O:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Br:8])=[CH:7][C:2]=1[B:20]([OH:25])[OH:21]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: COCOc1cc(OC)c(Br)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: COCOc1cc(OC)c(Br)cc1B(O)O
Temperature: 80 °C
Reaction time: 13 h
Yield: 88 %

Procedure:
In a glove box, to a 40 mL I-Chem vial equipped with a stir bar and containing 2-iodo-4-bromo-5-methoxy-1-methoxymethoxybenzene (500 mg, 1.34 mmol) was added potassium acetate (395 mg, 4.02 mmol), bis(neopentylglycolato)diboron (363 mg, 1.61 mmol) and PdCl2(dppf) (33 mg, 0.040 mmol). The vial was sealed with a septum cap and then removed from the glove box. To the vial was then added DMSO (11 mL) and the resulting mixture was sealed under an atmosphere of argon and stirred at 80° C. for 13 h. The mixture was then allowed to cool to 23° C. and 1 M aq. NaOH was added (0.9 mL, 0.9 mmol). The mixture was stirred at 23° C. for 10 minutes and then diluted with saturated aq. NH4Cl (50 mL), water (50 mL), and Et2O (100 mL). The layers were separated and the organic phase was washed with water (3×100 mL), dried over MgSO4, and concentrated in vacuo. The residue was thrice dissolved in MeCN and concentrated in vacuo to afford a crude sample of 2-methoxymethoxy-4-methoxy-5-bromophenyl boronic acid as a light brown solid (343 mg): TLC (EtOAc) Rf=0.50, stained by KMnO4; 1H—NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 6.75 (s, 1H), 5.97 (s, 2H), 5.29 (s, 2H), 3.91 (s, 3H), 3.52 (s, 3H). To this crude boronic acid dissolved in benzene:DMSO (10:1) was added N-methyliminodiacetic acid (210 mg, 1.43 mmol). The flask was fitted with a Dean-Stark trap and a reflux condenser and the mixture was refluxed with stirring for 11 h followed by concentration in vacuo. The resulting crude product was adsorbed onto Florisil gel from a MeCN solution. The resulting powder was dry-loaded on top of a silica gel column slurry-packed with Et2O. The column was flushed with a copious volume of Et2O and then the product was eluted with Et2O:MeCN 1:1 to yield building block 14 as an off-white solid (365 mg, 68% yield over two steps).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6]C=CC=1.NC1CCC[N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1>>[C:36]([O:35][C:33]([N:29]1[CH2:6][CH2:7][CH2:2][CH:1]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])[CH2:28]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2sccc2Nc2ncnc3[nH]ccc23)C1
Yield: 14 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using tert-butyl 3-aminopiperidine-1-carboxylate instead of benzylamine and obtained in 14% yield. 1H NMR (DMSO-d6) 11.96 (br s, 1H), 11.39 (br s, 1H), 8.47 (d, J=5.8 Hz, 1H), 8.38 (s, 1H), 8.09-8.01 (m, 1H), 7.78 (d, J=4.8 Hz, 1H), 7.38-7.14 (m, 1H), 6.48-6.43 (m, 1H), 3.91-3.75 (m, 3H), 2.80-2.62 (m, 3H), 1.92-1.84 (m, 1H), 1.75-1.66 (m, 1H), 1.65-1.54 (m, 1H), 1.40 (s, 9H); MS (m/z) 443 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[C@:34]([OH:38])([C:36]#[CH:37])[CH3:35].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:37]#[C:36][C@@:34]([OH:38])([C:29]6[N:30]=[CH:31][CH:32]=[CH:33][N:28]=6)[CH3:35])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: C#C[C@@](C)(O)c1ncccn1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[C@@](O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1)c1ncccn1
Yield: 40 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-10-[(3R)-3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with (2R)-2-pyrimidin-2-ylbut-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 47 mg of the titled compound (40% yield). M+1=501.2. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=4.8 Hz, 2H), 8.64 (d, J=8.4 Hz, 1H), 8.35 (br s, 1H), 7.74 (br s, 1H), 7.50 (t, J=4.8 Hz, 1H), 7.03 (d, J=10.5 Hz, 1H), 6.21 (s, 1H), 5.04-4.80 (m, 2H), 4.63-4.54 (m, 2H), 2.13-2.04 (m, 1H), 1.89 (s, 3H), 1.03-0.95 (m, 2H), 0.93-0.87 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[N:6]2[CH3:11].O[Li].O.OS([O-])(=O)=O.[K+]>C1COCC1.O>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cc2c(O)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 4-hydroxy-1-methyl-1H-indole-2-carboxylate (0.20 g) in THF (20 mL) was added LiOH.H2O (0.1 g) in water (20 mL) and the resulting two phase solution was stirred at room temperature under nitrogen for 4 hr. The reaction mixture was acidified with KHSO4 and the product was extracted into EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed over silica gel with a mixture of EtOAc and hexane to give 0.12 g of the title compound. MS ES (M++H)=192.
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:18]1[N:35]=[CH:34][C:21]2[NH:22][C:23](=[O:33])[N:24]([CH3:32])[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]=2[CH:19]=1>>[CH3:1][C:2]1[C:6]([C:18]2[N:35]=[CH:34][C:21]3[NH:22][C:23](=[O:33])[N:24]([CH3:32])[CH:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]=3[CH:19]=2)=[C:5]([CH3:10])[O:4][N:3]=1
Reactant: CN1C(=O)Nc2cnc(Cl)cc2C1c1ccccc1
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1-c1cc2c(cn1)NC(=O)N(C)C2c1ccccc1
Temperature: 90 °C

Procedure:
3,5-dimethylisoxazole-4-boronic acid (140 mg, 0.993 mmol), cesium carbonate (500 mg, 1.519 mmol) and 1,1-bis(diphenylphosphino)ferocene-palladium(II)dichloride dichloromethane complex are added to a microwave vessel flushed with argon. Dimethyl sulfoxide (5 mL) is added and the mixture purged with argon. Finally, 6-Chloro-3-methyl-4-phenyl-3,4-dihydro-1H-pyrido[3,4-d]pyrimidin-2-one (140 mg, 0.511 mmol) is added and the mixture again purged with argon and heated in a microwave oven at 90° C. for 120 minutes. The mixture is poured onto water and the aqueous phase extracted with dichloromethane. The organic phase is dried over magnesium sulfate. The drying agent is removed by filtration. The filtrate is concentrated to dryness and purified by chromatography on silica gel using a dichloromethane/methanol gradient. The product fractions are evaporated to dryness and purified by reverse phase HPLC. This affordes the desired product as a white solid.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3Br)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccn1
Reactant: OB(O)c1ccccc1
Product: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4ccccc4)CC3)n2)ccn1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “8” by using 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine and benzenboronic acid as the starting materials. LC-MS (M+H=523, obsd=523). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, J=5.1, 0.8 Hz, 1H), 8.08 (s, 1H), 7.76 (s, 1H), 7.54-7.46 (m, 3H), 7.43 (dd, J=5.1, 1.6 Hz, 1H), 7.36 (dddd, J=9.9, 6.5, 2.9, 1.6 Hz, 3H), 5.65 (s, 2H), 3.83 (t, J=6.2 Hz, 2H), 3.79-3.66 (m, 2H), 3.09 (t, J=7.0 Hz, 4H), 3.00 (h, J=6.9 Hz, 1H), 2.92-2.79 (m, 1H), 2.69 (dd, J=20.7, 7.0 Hz, 1H), 1.92 (p, J=7.0 Hz, 2H), 1.59 (dt, J=8.0, 4.5 Hz, 4H), 1.25 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:15][O:16]3)=[CH:11][C:10]=2[Cl:24])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[C:31]([CH3:38])[CH:32]=[CH:33][CH:34]=2)[N:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.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]>[Cl:24][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH:2][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[C:31]([CH3:38])[CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:26][CH:25]=1)[O:16][CH2:15][CH2:14][CH:13]2[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1cccc2ccc(Cl)nc12
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(Cl)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc5cccc(C)c5n4)cc3)c(Cl)cc21
Temperature: 60 °C
Yield: 69.8 %

Procedure:
To a solution of ethyl 7-(4-carbamoylphenoxy)-6-chlorochroman-4-carboxylate (0.025 g, 0.0665 mmol), 2-chloro-8-methylquinoline (0.0130 g, 0.0732 mmol), X-PHOS (0.0238 g, 0.0732 mmol), and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.00634 g, 0.0133 mmol) in THF (0.6 ml) was added tris(dibenzylideneacetone)dipalladium (0.0030 g, 0.0033 mmol), and the reaction was heated to 60° C. for 16 hours. The reaction was loaded directly onto silica gel and eluted with a gradient of 5-70% EtOAc/hexanes to yield the desired compound (0.024 g, 0.0464 mmol, 69.8% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:4]=2[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:2]1[C:3]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:4]=2[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2

Procedure:
4-Chloro-7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (98 mg, 0.30 mmol) and 1.5 mL of 0.5 M sodium methoxide in methanol was warmed to 60° C. overnight. The mixture was concentrated under nitrogen and partitioned between ether and water. The ether layer was washed with brine, dried and concentrated to give 94 mg of the title compound as a yellow oil. LC-MS 324.0 (M+1).
Reaction SMILES: [C:1]([CH:4]([C:14]1[N:22]2[C:17]([C:18](=[O:34])[NH:19][C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)=[N:21]2)=[C:16]([CH2:35][CH3:36])[N:15]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH3:31])[CH2:23][C:20]1[NH:19][C:18](=[O:34])[C:17]2=[C:16]([CH2:35][CH3:36])[N:15]=[C:14]([CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5][CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:22]2[N:21]=1
Reactant: CCc1nc(C(CCCc2ccccc2)C(C)=O)n2nc(Cc3ccc(OC)c(OC)c3)[nH]c(=O)c12
Agent: [BH4-]
Agent: [Na+]
Product: CCc1nc(C(CCCc2ccccc2)C(C)O)n2nc(Cc3ccc(OC)c(OC)c3)[nH]c(=O)c12

Procedure:
50 mg (0.10 mmol) of 7-(1-acetyl-4-phenylbutyl)-2-(3,4-dimethoxybenzyl)-5-ethyl-imidazo[5,1-f][1,2,4]triazin-4(3H)-one, analogously to Example 12 are reacted with 19 mg (0.50 mmol) of sodium borohydride to give 2-(3,4-dimethoxybenzyl)-5-ethyl-7-[1-(1-hydroxyethyl)-4-phenylbutyl]imidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: N1C=CC=CC=1.[FH:7].[CH2:8]([CH:15]1[CH2:17][N@@:16]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[F:7][C@H:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:17][NH:16][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: F
Reactant: Cc1ccc(S(=O)(=O)[N@]2CC2Cc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[N@@]2CC2Cc2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC[C@H](F)Cc2ccccc2)cc1

Procedure:
To a stirred solution of hydrogen fluoride-pyridine (13 mL) at 0° C. under nitrogen was added (S)-(+)-2-benzyl-1-(p-tolylsulfonyl)aziridine (2 g) in one portion. The cooling bath was removed briefly until reaction became exothermic and then returned. After an additional 5 min. the reaction mixture was poured onto 100 mL of cracked ice. The product was extracted into ether, washed carefully with saturated NaHCO3 and brine, dried over Na2SO4, and evaporated to a white solid. The solid was triturated with hexane, collected and washed with ether/hexane to give 1.7 g of the title compound. Mp 130-133° C.; MS ES (M++H)=308.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH:20]([OH:26])[CH2:19]2.Cl>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:26][CH:20]3[CH:21]4[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]4)[CH2:19]3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc2c1ncn2Cc1ccccc1
Reactant: OC1CN2CCC1CC2
Agent: Cl
Product: c1ccc(Cn2cnc3c(OC4CN5CCC4CC5)nccc32)cc1
Yield: 48.6 %

Procedure:
Following the procedure of Example 1, 1-benzyl-4-chloro-1H-imidazo[4,5-c]pyridine (0.78 g, 3.2 mmol) was treated with 3-quinuclidinol (0.44 g, 3.5 mmol) to give 0.52 g (39%) of the title compound as the hydrochloride, 2.5 hydrate: mp 162°-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[C:11]1([CH:10]=[N+:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O-:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ONc1ccccc1Cl
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: [O-][N+](=Cc1ccccc1)c1ccccc1Cl

Procedure:
o-Chlorophenylhydroxylamine (0.05 moles) was dissolved in warm 95% ethanol (20 cc) and was treated with benzaldehyde (0.05 moles) with vigorous stirring. The solid which formed was from ethanol to give α-phenyl-N-2-chlorophenylnitrone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.O.ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C1COCCN1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N5CCOCC5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 77.9 %

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (Compound 1) (0.432 g, about 0.972 mmol), morpholine (0.11 mL, 1.263 mmol), DIEA (0.18 mL, 1.04 mmol) and HATU (0.342 g, 0.899 mmol) were added to a mixed solvent of DMF (4.5 mL) and dichloromethane (4.5 mL). The mixture was stirred at room temperature for 7 hr. Water and ethyl acetate were added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to produce a crude yellow solid, which was washed with methanol and ethyl ether to produce a purified product (0.371 g) in 77.9% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[BH4-].[K+]>CO>[C:10]1([CH:8]([CH:5]2[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]2)[OH:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1cccc2ccccc12)C1CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: OC(c1cccc2ccccc12)C1CCNCC1

Procedure:
To a solution of 60 g (0.22 mole) of 1-naphthyl 4-piperidyl ketone hydrochloride in 500 ml of methanol, 35 g (0.65 mole) of potassium borohydride is added gradually while stirred in an ice bath and the mixture reacted for 18 hours. The mixture is concentrated in vacuo, the residue partitioned between chloroform and water, and the organic phase dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield α-(1-naphthyl)-4-piperidinemethanol, which is dissolved in chloroform and an excess of dry HCl bubbled into the solution. The resulting precipitate is recrystallized from methanol/butanone to yield α-(1-naphthyl)-4-piperidinemethanol hydrochloride. M.P. 219°-21°.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:36]CCl>C(O)C>[ClH:36].[CH:29]1[C:20]2[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:18]([CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:19]=2[CH:32]=[CH:31][CH:30]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCCN2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above ester (0.4 g, 0.92 mmol) was dissolved in ethanol (10 ml) and a 4 N sodium hydroxide solution (0.70 ml) was added. The mixture was stirred at room temperature for 4 h. A 4 N hydrochloric acid solution was added until pH 1. Dichloromethane (300 ml) was added and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated with acetone, dissolved in a mixture of ethyl acetate and acetone and left for crystallization. This afforded 0.13 g of the title compound as a solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21](=[O:26])[CH:20]=1>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21](=[O:26])[CH:20]=1
Reactant: Cn1ccc(CN)cc1=O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1=O
Yield: 86.2 %

Procedure:
(4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (130 mg, 0.40 mmol), 4-aminomethyl-1-methyl-1H-pyridin-2-one (55 mg, 0.40 mol) were coupled in N,N-dimethylformamide (2 mL) at room temperature. The reaction mixture is diluted with water and the precipitate is collected by Büchner filtration and then dried under house vacuum to give (4Z)-6-iodo-4-({[(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as an orange solid (0.15 g, 88%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[C:16]3[CH2:17][CH2:18][N:19]4[C@H:23]([C:24]=3[N:25]=2)[CH2:22][CH2:21][CH2:20]4)=[CH:9][CH:8]=1)=[O:5])[CH3:2].B(O)O.C([O-])(=O)C.[K+].C(#N)C>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>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[C:16]3[CH2:17][CH2:18][N:19]4[C@@H:23]([C:24]=3[N:25]=2)[CH2:22][CH2:21][CH2:20]4)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN2CCC[C@@H]32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: OBO
Solvent: CC#N
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN2CCC[C@H]32)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
and 1-ethyl-3-(4-((S)-4-((S)-3-methylmorpholino)-5,6,8,9,10,10a-hexahydropyrimido[5,4-g]indolizin-2-yl)phenyl)urea (wq2): [4-Ethylureido)phenyl]boronic acid, pinacol ester (0.287 g, 0.000989 mol) (3S)-4-(2-chloro-5,6,8,9,10,10a-hexahydropyrimido[5,4-g]indolizin-4-yl)-3-methylmorpholine (0.251 g, 0.000813 mol), Tetrakis(triphenylphosphine)palladium(0) (0.04696 g, 4.064E-5 mol) Sodium carbonate (0.138 g, 0.00130 mol) and Potassium acetate (0.145 g, 0.00148 mol) were combined, nitrogen purged three times, added dry Acetonitrile (7.00 mL, 0.134 mol) followed by deoxygenated Water (4.00 mL, 0.222 mol), heated at 90° C. and stirred overnight. Added Tetrakis(triphenylphosphine)palladium(0) (0.062 g, 0.000054 mol) Sodium carbonate (0.059 g, 0.00056 mol) Potassium acetate (0.061 g, 0.00062 mol) Acetonitrile (3.50 mL, 0.0670 mol). The reaction mixture was heated at 120° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, and, chromatographed through silica gel (12 g, 0-10% MeOH in dichloromethane), purified by HPLC, and the diastereomers were separated by SFC. R-Diastereomer (wq1): 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.16 (t, J=9.2, 2H), 7.47 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.16-4.05 (m, 1H), 3.86 (d, J=11.2, 1H), 3.78-3.66 (m, 2H), 3.65-3.54 (m, 2H), 3.49-3.40 (m, 2H), 3.17-3.06 (m, 2H), 3.05-2.89 (m, 3H), 2.87-2.75 (m, 1H), 2.75-2.60 (m, 2H), 2.37 (dd, J=15.5, 7.5, 1H), 1.84-1.71 (m, 3H), 1.17 (d, J=6.6, 3H), 1.12 (t, J=7.2, 2H). LC/MS-m/z+437.2 (M+H)+; S-Diastereomer (wq2): 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.17 (d, J=8.7, 2H), 7.48 (d, J=8.7, 2H), 6.17 (t, J=5.3, 1H), 4.06 (s, 1H), 3.87 (d, J=11.2, 1H), 3.77 (d, J=7.7, 1H), 3.64 (dd, J=19.2, 10.4, 4H), 3.43-3.34 (m, 2H), 3.19-3.07 (m, 2H), 2.90 (dd, J=14.5, 8.1, 2H), 2.84-2.73 (m, 2H), 2.69 (d, J=10.8, 1H), 2.35 (d, J=8.5, 1H), 1.85-1.68 (m, 3H), 1.30 (d, J=6.6, 3H), 1.07 (t, J=7.2, 3H). LC/MS-m/z+437.2 (M+H)+.