Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70]([NH:72][CH2:73][C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[ClH:45].[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:72][CH2:73][C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol. (Intermediate FC) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113). MS (ES+) m/e 729.54 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][C:6]2[CH2:7][C:8](=[O:27])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:26])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:33]>>[CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][C:6]2[C:7](=[O:33])[C:8](=[O:27])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:26])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=[Se]=O
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCCSc1ccccc1)CC2
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCN(C)CCCSc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(phenylthio)-propyl]-methylamine and selenium dioxide analogously to Example 55.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([O:15][CH3:16])[N:4]=1.[F:17][C:18]([F:28])([C:24]([F:27])([F:26])[F:25])/[CH:19]=[CH:20]/[C:21](O)=[O:22].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:21](=[O:22])/[CH:20]=[CH:19]/[C:18]([F:17])([F:28])[C:24]([F:25])([F:26])[F:27])[CH2:13][CH2:14]2)[CH:6]=[C:5]([O:15][CH3:16])[N:4]=1
Reactant: COc1cc(N2CCNCC2)cc(OC)n1
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C(=O)/C=C/C(F)(F)C(F)(F)F)CC2)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
1-(2,6-Dimethoxy-4-pyridyl)piperazine (30 mg, 0.13 mmol) was dissolved in anhydrous dichloromethane (2 ml) together with (E)-4,4,5,5,5-pentafluoropent-2-enoic acid (35 mg, 0.18 mmol), triethylamine (31 mg, 44 μl, 0.32 mmol), HBTU (74 mg, 0.15 mmol) and stirred at room temperature for two hours. The mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 9 mg of a solid (0.023 mmol, 15%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][CH2:29][CH2:30][OH:31].[I-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: OCCCCCl
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1ccn2c3ccc(Br)cc3c3cc(OCCCCO)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (12 ml), and potassium carbonate (220 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 4-chloro-1-butanol (0.095 ml) and potassium iodide (1 grain) were added to the mixture. The mixture was stirred at 80° C. in a hot water bath for 24 hours, and the reaction mixture was poured into ice water (100 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride/methanol=20:1) to obtain the title compound (160 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]=1[F:1])=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(S(N)(=O)=O)cc1F
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)c(F)c1
Temperature: 0 °C

Procedure:
2-Fluoro-4-sulphamoyl-aniline (7.6g) and α-chloroacetyl chloride (12.0g) were refluxed together for 60 min. The reaction product was ground in a mortar with ice/water and filtered (8.3g). Recrystallisation from ethyl acetate to give beige needles m.p. 185°-187°
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.O1CCCC1.[Br-].[F:18][C:19]1([F:27])[CH2:24][CH2:23][CH:22]([CH2:25][Zn+])[CH2:21][CH2:20]1>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:18][C:19]1([F:27])[CH2:24][CH2:23][CH:22]([CH2:25][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=2)[C:3]([O:2][CH3:1])=[O:11])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: FC1(F)CCC(C[Zn+])CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(CC2CCC(F)(F)CC2)c1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
To methyl-2-chloroisonicotinate (1.664 g, 9.7 mmol) and bis(tri-tert-butylphosphine)palladium(0) (198 mg, 0.38 mmol) under nitrogen was added tetrahydrofuran (10 mL). To the resulting solution was added freshly prepared ((4,4-difluorocyclohexyl)methyl)zinc(II) bromide (14.55 mmol, 0.5 M in 29 mL DMA) and the resulting brown mixture heated to 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed with satd NaHCO3 (2 times), satd NH4Cl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH. The NH3/MeOH layer was evaporated leaving methyl 2-((4,4-difluorocyclohexyl)methyl)isonicotinate (2 g, 67%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 1.30-1.46 (m, 2H), 1.58-1.79 (m, 4H), 1.87-2.14 (m, 3H), 2.82 (d, 2H), 3.96 (s, 3H), 7.65-7.73 (m, 2H), 8.70 (d, 1H). MS m/z 270 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[C:7]([F:10])=[CH:8][CH:9]=1)=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc(F)c(N=Cc2cccc(Br)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-4-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: [SH:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[C:12](O)(=[O:17])[CH2:13][C:14](O)=[O:15].C(OC(=O)C)(=O)C>C(O)(=O)C>[OH:17][C:12]1[C:3]2[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=2[S:1][C:14](=[O:15])[CH:13]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cn1c(S)cc(=O)n(C)c1=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c(=O)c2c(O)cc(=O)sc2n(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of Step 2 intermediate (12.75 g, 74.127 mmol), malonic acid (9.30 g, 88.953 mmol), acetic acid (7.41 ml) and acetic anhydride (16.8 ml) was heated to 80° C. under nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and quenched with water (50 ml). Precipitated solid was filtered, washed with water (2×50 ml) and dried well to obtain 14.4 g of the product as brown solid; 1H NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H), 3.48 (s, 3H), 5.73 (s, 1H), 13.76 (br s, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O>CCOCC>[NH2:4][C:5]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:6]=1[C:7]([CH3:1])([OH:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC(O)(c1ccccc1)c1cc(Cl)ccc1N
Reaction time: 8 h
Yield: 75 %

Procedure:
Methylmagnesium bromide (267 ml of 3M ether-solution; 0.8 mole) is added during 45 minutes to a solution of 2-amino-5-chlorobenzophenone (46.3 g; 0.2 mole) in 1 liter of ether. The mixture is refluxed for 5 hours and allowed to stand overnight. It is then cooled in ice and decomposed with 400 ml of water. The ether layer is decanted, washed with saturated salt solution dried (MgSO4) and evaporated. The residue is crystallized from ether-Skellysolve B to give 37.1 g (75% yield), mp 93°-94° C., unchanged on recrystallization. Spectral data support the product structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=2[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])=[C:5]([F:25])[CH:4]=1)#[CH:2]>C1COCC1.CO.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=2[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])=[C:5]([F:25])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Reaction time: 14.8 h

Procedure:
A mixture of the product of Example 7A, 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxy-ethoxy)benzamide (11.0 g, 31.40 mmol), Pd—C (10%, 1.0 g) in THF (100 mL) and MeOH (100 mL) was subject to hydrogenation (25 psi) for 14.8 hrs (The reaction was followed by HPLC until all SM peak disappeared.). The mixture was filtered through Celite® and the filtrates were concentrated to give a light yellow solid. The solid was recrystallized from heptane-EtOAc to give the title compound as a white solid, 6.97 g, 62.8%, mp 112–112.5° C. Anal.: C, 58.00 (57.63); H, 4.99 (4.84); N, 7.59 (7.91); F, 15.55 (16.09).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:8](=[C:9]([OH:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[CH2:15](I)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:15]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[OH:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1cccc2c(O)cccc12
Reactant: CCCCCCCCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCOc1cccc2c(O)cccc12
Reaction time: 4 h

Procedure:
12 g (0.3 Mol) sodium hydroxide are dissolved while heating in 500 ml ethanol and a solution of 25 g (0.15 Mol) 1,5-dihydroxynaphthalene 97% is added to the cooled solution within 20 minutes. Afterwards 40.23 g (0.15 Mol) n-decyl iodide is added dropwise within 20 minutes and it is subsequently boiled for 4 hours under reflux. After aspiration of the inorganic residue, the filtrate is concentrated in a vacuum and the dark-brown, semi-crystalline residue is purified by column chromatography on silica gel 60 (Merck). Mobile solvent: toluol/methanol=7:1. After recrystallization from n-heptane the corresponding eluate yields 11.5 g (25.3% of the theroretical yield) product, light-brown crystals, Fp 85°-87° C.
Reaction SMILES: Cl.Cl.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(OC(C)C)OC(C)C>>[CH3:29][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH:14][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC(C)OB(OC(C)C)c1cccs1
Reactant: Cc1cc(Nc2ncnc3ccc(Br)cc23)ccc1OCc1ccccn1
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(-c4cccs4)cc23)ccc1OCc1ccccn1
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt was reacted with di-isopropyl 2-thienylboronate to give 4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-(2-thienyl)-quinazoline in 70% yield, m.p. 205°-206° C.;
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>>[Cl:1][C:2]1[C:3]([C:4]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][CH3:11])=[CH:14][C:15]=2[N+:20]([O-:22])=[O:21])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccnc1Cl
Product: COc1ccc(NC(=O)c2cccnc2Cl)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-chloronicotinoyl chloride and 4-methoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 10.76 (s, 1H), 8.78 (d, J=9.3, 1H), 8.58-8.55 (m, 1H), 8.13-8.09 (m, 1H), 7.73 (d, J=3.0, 1H), 7.45-7.40 (m, 1H), 7.34-7.28 (m, 1H0, 3.90 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][NH2:24].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][NH:24][C:32](=[O:34])[CH3:33]
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCN
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCNC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
2-{[6-Methoxy-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 32, 2.0 g, 5.8 mmol) in DCM (100 mL) was treated with triethylamine (2.4 mL, 17 mmol) and 4-dimethylaminopyridine (0.35 g, 2.9 mmol). The solution was cooled to 0° C. and acetyl chloride (0.82 mL, 12 mmol) was added. The mixture was stirred at room temperature for 1 hour, washed with aqueous saturated NaHCO3 (20 mL) and 1 M HCl (2×20 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (1.2 g). MS m/z 389 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([N:28]=[S:29]([CH3:32])([CH3:31])=[O:30])=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][N:18]=1)C1C=CC=CC=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH3:32][S:29](=[N:28][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[OH:8])=[N:18][CH:19]=[N:20]2)=[C:25]([CH3:27])[CH:24]=1)([CH3:31])=[O:30]
Reactant: Cc1cc(N=S(C)(C)=O)cc2ncnc(Nc3ccc(F)cc3OCc3ccccc3)c12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N=S(C)(C)=O)cc2ncnc(Nc3ccc(F)cc3O)c12
Reaction time: 0.25 h

Procedure:
3.5 g (7.8 mmol) of N-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-5-methyl-quinazolin-4-amine in DCM are cooled to 0° C., 0.9 ml (9.3 mmol) boron tribromide are added dropwise and the reaction mixture is stirred for 15 min. Water is added cautiously and the aqueous layer is separated and extracted with DCM. The organic phases are pooled, washed with water, dried and evaporated. The residue is treated with isopropanol, filtered and dried.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f10) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[NH:10][C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:8])(=[O:19])[CH3:18]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(=O)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cccc(NC(=O)c2cc(C)on2)c1

Procedure:
A solution of 5-methyl-3-isoxazolecarbonyl chloride (14.5 g) in acetone (30 ml) was added to a solution of m-aminoacetophenone (13.8 g) in acetone (280 ml) in the presence of anhydrous potassium carbonate (21.0 g). The mixture was stirred for 1/2hour, and then diluted with water. The precipitated product was filtered, washed with water and dried. Yield = 20.5 g (83%), m.p. 188°-190°.
Reaction SMILES: [CH2:1]([C:3](=[CH:9][CH2:10][O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH2:13]1)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[CH2:1]([C:3](=[CH:9][CH2:10][O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH2:13]1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
0.5 g of ethyl 2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}but-2-enoate is dissolved in 5 ml of methanol, and 2.5 ml of a 1N aqueous sodium hydroxide solution are added. After 12 h of stirring at room temperature, the mixture is acidified with 3 ml of 1 N hydrochloric acid and the resulting precipitate is taken up in ethyl acetate. The solvent is removed under reduced pressure and the residue of the ester hydrolysis, 2-ethyl4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxy}but-2-enoic acid, is obtained as 0.45 g of a white solid. C23H28FNO5 (417.48) MS(ESI): 418 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:15][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)SCC[C@H]2N
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)c1ccc2c(c1)SCC[C@H]2NC(=O)OCc1ccccc1

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using (R)-4-aminothiochromane-7-carboxylic acid methyl ester (5.70 g) and benzyloxycarbonyl chloride (5.50 ml), the objective (R)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (7.35 g) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:27][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.[OH:39][C:40]1[C:48]2[N:47]=NN[C:44]=2[CH:43]=[CH:42]C=1.C(N(CC)CC)C.[C@@H]12O[C@@H](CC1)CNC2>CN(C)C=O.CN(C)C1C=CN=CC=1>[C@@H:43]12[CH2:44][C@@H:48]([N:47]([C:24]([C@@H:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:15]4[N:14]=[C:13]5[NH:27][C:10]([C:8]6[CH:7]=[CH:6][N:5]=[C:4]([CH:1]7[CH2:3][CH2:2]7)[N:9]=6)=[N:11][C:12]5=[CH:17][CH:16]=4)[CH2:19]3)=[O:25])[CH2:42]1)[CH2:40][O:39]2
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Agent: C1C[C@H]2CNC[C@@H]1O2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1C[C@H]2C[C@@H]1CO2
Temperature: 0 °C
Reaction time: 18 h
Yield: 10.5 %

Procedure:
To a solution of (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (70 mg, 0.192 mmol) in N,N-dimethylformamide (10 mL) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCl) (73.2 mg, 0.383 mmol), hydroxybenzotriazole (52 mg, 0.383 mmol), triethylamine (58.2 mg, 0.575 mmol), (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane (186 mg, 1.64 mmol) and 4-dimethylaminopyridine (3 mg) at room temperature. The reaction mixture was stirred for 18 h, poured into ice water, extracted with ethyl acetate, washed with cold water and concentrated. The crude was purified via preparative TLC (3% methanol in dichloromethane) to afford the title compound (9 mg). MS (ES+) (M+H) 446.3; LCMS retention time 1.816 min (Method F)