Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and pyrrolidine according to conditions described in general procedure C. Mp: 111-113° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58 (s, 6 H), 1.81 (bs, 4 H), 3.03-3.40 (m, 8 H), 6.15 (d, J=5.5, 1 H), 6.95 (d, 1 H), 7.15 (d, 1 H), 7.40 (d, J=8.4 Hz,1 H), 7.46 (s, 1 H), 7.50-7.60 (m, 3 H), 7.82-7.86 (m, 1 H), 7.97-7.99 (m, 1 H), 8.21-8.23 (m, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:19]>O>[Ag+:19].[CH2:1]([O:8][CH2:9][C:10]([O-:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COCc1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To a solution of 2-(benzyloxy)acetic acid (3.58 g, 21.5 mmol) in water (108 mL) at 0° C. was added aqueous NaOH (1.000N, 21.5 mmol). The cold bath was removed, and the reaction was stirred to room temperature for 0.25 h. After the reaction vessel was wrapped in aluminum foil, a solution of silver nitrate (4.07 g, 24.0 mmol) in water (40 mL) was added over 10 min. After 1 h, the precipitate was filtered, washed and dried over P2O5 in a dessicator to give the title compound as an off-white solid (4.90 g, 84% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:22]=[CH:21][C:10]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=4)=[N:12][S:13][C:9]=3[CH:8]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and azetidine were converted to yield 6-(4-Azetidin-1-yl-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS: 418 (MH+, 1Br).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[F:16][C:17]([F:26])([F:25])[CH:18]1[NH:23][C:22]([NH2:24])=[N:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:24]=[C:22]3[NH:23][CH:18]([C:17]([F:26])([F:16])[F:25])[CH2:19][CH2:20][N:21]3[C:9](=[O:11])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: NC1=NCCC(C(F)(F)F)N1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCC(C(F)(F)F)N2
Yield: 55.9 %

Procedure:
A mixture of 5.62 g (29.09 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 7 g (29.09 mmol) of 6-(trifluoromethyl)-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2) and 10.05 g (72.72 mmol) of potassium carbonate in 50 ml of ethanol was heated at reflux temperature for 12 h. The cooled solution was evaporated to remove solvent, the residue was treated with water and the precipitate was filtered to give 4.82 g of product as a yellow powder.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@H:5]2[C:9]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C@H:4]12.[Br:19]Br>C(O)(=O)C>[Br:19][C:13]1[C:10]2[O:11][CH2:12][C@@H:4]3[C@@H:3]([CH2:2][OH:1])[CH2:8][NH:7][CH2:6][C@H:5]3[C:9]=2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: COc1ccc2c(c1)[C@@H]1CNC[C@H](CO)[C@H]1CO2
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(Br)c2c(c1)[C@@H]1CNC[C@H](CO)[C@H]1CO2
Reaction time: 1.5 h

Procedure:
To a stirred solution of 8.66 g (±)-[4R*,4aS*,10bR*]-4-(hydroxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2H-[1]benzopyrano[4,3-c]pyridine in 90 ml acetic acid is added dropwise 1.96 ml bromine at 25°. After stirring 1.5 h, the solution is concentrated under reduced pressure and treated with 100 ml 2N NaOH. The aqueous phase is extracted with three 100 ml portions of CH2Cl2. The organic extracts are dried over Na2SO4, filtered, concentrated and flash chromatographed with CH2Cl2 /ammonia saturated methanol (90:10) to give the title compound as the major product; m.p. 281°-285° dec (HCl salt).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O.Cl[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1>COCCOC.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][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: COc1cc(OC(F)(F)F)ccc1B(O)O
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: COCCOC
Solvent: O
Product: COc1cc(OC(F)(F)F)ccc1-c1ncc([N+](=O)[O-])cc1C
Temperature: 85 °C
Reaction time: 19 h

Procedure:
2-methoxy-4-trifluoromethoxybenzene boronic acid (72 g, 0.31 mol), K2CO3 (80.16 g, 0.58 mol) and water (100 ml) are added to a solution of 2-chloro-3-methyl -5-nitro-pyridine (50 g, 0.29 mol) in DME (500 ml) at room temperature. Pd(Ph3P)4 (3.35 g, 2.9 mmol) is added and the mixture is stirred at 85° C. for 19 hours. 500 ml of water is added and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue is purified by flash column chromatography (hexane/EtOAc 9:1) to obtain 2-(2-methoxy-4-trifluoromethoxy-phenyl)-3-methyl-5-nitro-pyridine. Rf (hexane/EtOAc=9:1)=0.41.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3Cl)[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17].Cl>CS(C)=O.O.C(Cl)Cl.CCOC(C)=O>[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:9])[CH:4]=3)[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1ccc(O)cc1F
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)c(F)c4)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 4-amino-3-fluorophenol (19) in DMSO (12 mL) was added potassium tert-butoxide (0.824 g, 7.34 mmol). After 30 min, intermediate 11 (2.451 g, 5.65 mmol) was added and the reaction mixture was heated at 100° C. for 1.5 h, cooled to room temperature, poured in water (50 mL) at 40-45° C. and stirred for 30 min. EtOAc (40 mL), DCM (40 mL) and water (40 ml) were added and the pH was adjusted to 7 by addition of HCl. Solids were removed by filtration through a paper filter and the two phases were separated. The organic layer was collected, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent DCM/MeOH: 99/1, 98/2, 95/5), to afford intermediate 20 (0.952 g, 32% yield). MS (m/z): 525.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCNC2
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCN(C(=O)C(C)C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) was added isobutyryl chloride (0.013 mL, 0.124 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, warmed to 23° C. and stirred for an additional 15.5 h. The reaction mixture was concentrated via rotary evaporation and partitioned between EtOAc (4 mL) and NH4Cl (2 mL). The layers were separated and the organic phase was washed with brine (2 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in EtOAc and MeOH, adsorbed on silica gel (0.25 g), and purified via medium pressure chromatography using a 50% to 100% gradient of EtOAc in heptane on a 4 g silica gel column (Single Step™) to give the title compound (39.3 mg, 66.9%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 0.99 (d, J=6.8 Hz, 2.7H), 1.03 (d, J=6.8 Hz, 3H), 1.11-1.22 (m, 6H), 2.58 (br s, 3.8H), 2.69 (t, J=5.4 Hz, 1.2H), 2.88-3.13 (m, 5H), 3.58 (s, 2H), 3.75 (dt, J=10.9, 5.6 Hz, 2H), 4.05-4.17 (m, 1H), 4.41 (s, 1.1H), 4.49 (s, 0.9H), 5.29-5.42 (m, 1H), 7.08 (td, J=8.5, 2.4 Hz, 1H), 7.21 (td, J=9.9, 2.7 Hz, 1H), 7.44-7.52 (m, 1H); ESI-MS m/z [M+F]+ 473.0.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ccc(C(F)(F)F)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-trifluoromethyl-pyridine following a procedure analogous to that described for Example 79. LC (method 7): tR=1.63 min; Mass spectrum (ESI+): m/z=509 [M+H]+.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]2=3)[CH2:19][CH2:20]1
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: ClCCN1CCOCC1
Product: O=c1ccsc2c3ccccc3n(CCN3CCOCC3)c12
Yield: 68 %

Procedure:
4.8 g of thiopyrano [3,2-b]indol-4(5H)-one and 15 g of chloroethylmorpholine, are reacted in the same manner as described in Example 14, except that the crude free base crystallized. This is filtered and recrystallized from methylenechloride-hexane to give 5.1 g of product, mp 136°-137°C.
Reaction SMILES: [Na+].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])[C:23]([O-:25])=[O:24])=[CH:18][CH:17]=1.Cl>ClCCl>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1
Reactant: O=C([O-])C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid sodium salt (3.0 g), dichloromethane (500 mL), and 1N hydrochloric acid (25 mL) was stirred for one hour until all solids dissolved. The layers were separated, the water layer was extracted 2×100 mL of dichloromethane and the organic layers were washed in turn with water. The combined organic layers were dried (Na2SO4), filtered and evaporated to give 2.8 g of crude product. Crystallization from dichloromethane-hexane provided 2.6 g of 4[[2- (2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 170°-171° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19](CC3C=CC(OC)=CC=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:9][CH:8]=1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:30])[N:17]2[CH3:31])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Trifluoroacetic acid (110 mL) is added dropwise to a solution of 2-Butoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (5.31 g, 10.1 mmol) and triethylsilane (3.22 mL, 20.2 mmol, d=0.728). The reaction mixture is stirred at ambient temperature for 4 h, concentrated in vacuo, and diluted with ethyl acetate. The solution is washed, then dried, concentrated, and purified by flash chromatography to provide the title compound (4.1 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.09 (d, 2H, J=8.4 Hz), 6.74 (d, 2H, J=8.4 Hz), 5.36 (s, 1H), 4.17-4.07 (m, 2H), 4.02-3.96 (m, 2H), 3.76-3.68 (m, 2H), 3.55 (t, 1H, J=8.8 hz), 3.40-3.31 (m, 2H), 3.20 (t, 1H, J=8.0 Hz), 2.95, 2.91 (ABq, 2H, J=13.6 Hz), 2.76 (s, 3H), 2.24-2.18 (m, 1H), 1.97-1.88 (m, 1H), 1.58-1.51 (m, 2H), 1.41-1.31 (m, 2H), 1.27 (s, 3H), 1.22 (t, 3H, J=7.2 Hz), 0.89 (t, 3H, J=7.2 Hz). Rf=0.44 in 10% CH3OH in CH2Cl2.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:26])=[O:16])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCCCN2CCCCC2)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1C(F)(F)F

Procedure:
4-(3-Piperidin-1-yl-propoxy)-2-trifluoromethyl-benzoic acid (D5) (0.9 g) was heated at reflux in thionyl chloride (20 ml) for 2 h. The reaction mixture was evaporated to a minimum then co-evaporated with DCM (3×) to give the title compound (D6) as a white solid (1.0 g)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:9][C:8](=[O:10])[NH:7][C:6]([CH3:12])([CH3:11])[CH2:5]1.[Cl:13]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCl.CO>[Cl:13][N:7]1[C:6]([CH3:12])([CH3:11])[CH2:5][CH:4]([CH2:3][CH2:2][OH:1])[O:9][C:8]1=[O:10]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: CC1(C)CC(CCO)OC(=O)N1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC(CCO)OC(=O)N1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a solution of 6-(2-hydroxyethyl)-4,4-dimethyl-1,3-oxazinan-2-one (278 mg, 1.6 mmol) in 4 mL dichloromethane and 250 uL methanol was added trichloroisocyanuric acid (370 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 4 hours and then directly purified by column chromatography (0 to 10% methanol in dichloromethane) to give a white solid (291 mg, 1.40 mmol, 87%). 1H NMR (D2O, 400 MHz) δ 1.35 (s, 6H), 1.78-1.83 (m, 2H), 1.97-2.03 (dd, J=11.9, 14.2 Hz, 1H), 2.13-2.17 (dd, J=2.1, 14.2 Hz, 1H), 3.64-3.68 (m, 2H), 4.55-4.60 (m, 2H). 13C NMR (D2O, 100 MHz) δ 24.3, 27.9, 35.8, 41.5, 63.0, 72.5, 155.15. LRMS (ESI/APCI) m/z 208 [M+H]+.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[F:34][C:35]1[C:43]2[CH:42]=[C:41]([C:44](=[O:47])[CH2:45][CH3:46])[S:40][C:39]=2[CH:38]=[CH:37][CH:36]=1>O1CCCC1>[Br:1][CH:45]([CH3:46])[C:44]([C:41]1[S:40][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([F:34])[C:43]=2[CH:42]=1)=[O:47]
Reactant: CCC(=O)c1cc2c(F)cccc2s1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1cc2c(F)cccc2s1
Temperature: 0 °C
Reaction time: 5 h
Yield: 154.4 %

Procedure:
Phenyltrimethylammonium tribromide (0.98 g) was added in portions under nitrogen at 0° C. over 10 minutes to a stirred solution of 1-(4-fluorobenzo[b]thiophen-2-yl)propan-1-one (0.54 g) in tetrahydrofuran (15 ml) then the mixture was stirred at 0° C. for 5 hours. Further phenyltrimethylammonium tribromide (0.49 g) was added, and the mixture was stirred at 0° C. for 3 hours then allowed to stand at ambient temperature for 12 hours. Further phenyltrimethylammonium tribromide (0.49 g) was added, the mixture was stirred at ambient temperature for 3 hours, then it was filtered through a bed of silica. The solvent was removed in vacuo to give 2-bromo-1-(4-fluorobenzo[b]thiophen-2-yl)propan-1-one (0.67 g) as a colourless solid which was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)[CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1ccc(-c2cncc(CCl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cncc(COc3ccc(CCCCn4ccnn4)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of 37 mg (0.17 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 3-Chloromethyl-5-(4-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 36 mg (46%) of the title compound as light brown powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:26]=3)[C:23](O)=[O:24])[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:27])=[N:3]1.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=1)(=[NH:31])=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:26]=[C:22]([C:23]([N:31]=[S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:37]=4)([CH3:28])=[O:30])=[O:24])[CH:21]=[N:20][CH:19]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: COC(=O)CCc1ccc(S(C)(=N)=O)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)O)c3)c2)n(C)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)cc1
Temperature: 50 °C
Yield: 44.7 %

Procedure:
A solution of 5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)-ethynyl]nicotinic acid (0.149 g, 0.414 mmol) in DMF (4 mL) was treated with methyl 3-(4-(S-methylsulfonimidoyl)phenyl)propanoate (0.100 g, 0.414 mmol), followed by BOP (0.238 g, 0.539 mmol) and DIPEA (0.144 mL, 0.830 mmol). The reaction mixture was heated to 50° C. for 3 h. After allowing the reaction to cool to room temperature it was taken up in EtOAc (10 mL) and extracted with brine (3×10 mL). The EtOAc layer was then washed with saturated aqueous Na2CO3 (2×10 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated. The crude residue was purified via column chromatography (silica gel, gradient elution, EtOAc in Hexanes: 0% to 100% EtOAc) affording the title compound (0.108 g, 45%).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.N([O-])=O.[Na+].[ClH:29]>O>[Cl:29][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: CCCc1c2c(c(N)c3c(=O)cc(C(=O)OCC)oc13)CCCC2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCc1c2c(c(Cl)c3c(=O)cc(C(=O)O)oc13)CCCC2
Reaction time: 0.25 h

Procedure:
Ethyl 5-amino-6,7,8,9-tetrahydro4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (7.2 g) in concentrated hydrochloric acid (80 ml) was treated with sodium nitrite (1.8 g) in water (15 ml) with stirring at 0° over 15 minutes.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36]>>[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][CH2:18]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: Nc1ccccc1N
Product: CC(C)(O)C1CCN(Cc2ccc3nc(Nc4ccccc4N)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.12 g) was reacted with diaminobenzene via General Procedure C to afford crude 2-(1-((2-(2-aminophenylamino)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol after elution thru a Biotage isolute scx-2 cartridge.