Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:31]1[N:36]=[C:35]([NH:37][C:38]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:39]=2[C:40]([NH:42][CH3:43])=[O:41])[C:34]([Cl:49])=[CH:33][N:32]=1>C(O)(C)C>[Cl:49][C:34]1[C:35]([NH:37][C:38]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:39]=2[C:40]([NH:42][CH3:43])=[O:41])=[N:36][C:31]([NH:29][C:27]2[CH:26]=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:32][CH:33]=1
Reactant: CCN1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21
Yield: 42.5 %

Procedure:
10-Camphorsulfonic acid (91 mg, 0.39 mmol) was added to 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (65 mg, 0.34 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (110 mg, 0.34 mmol) in Isopropyl alcohol (3 mL). The mixture was irradiated in a CEM microwave (130° C., 40 min) Complete conversion was achieved. The reaction was diluted with 5 mL satd. sodium bicarbonate and the ppt collected. The ppt was purified by ISCO (12 g SiO2, 0-100% EtOAc:Hex) to afford 2-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide as a green foam (68 mg, 43%). LCMS: 471 (M+H), 1H-NMR (CDCl3): 8.64 (s, 1H), 8.03 (s, 1H), 7.29 (m, 3H), 7.10 (s, 1H), 6.88 (m, 1H), 6.68 (m, 2H), 6.07 (q, 1H, J=4.5 Hz), 4.03 (t, 2H, J=5.6 Hz), 3.17 (m, 4H), 2.91 (d, 3H, J=4.5 Hz), 1.99 (m, 2H), 1.16 (t, 3H, J=7.0 Hz); 19F-NMR: −112
Reaction SMILES: COCCOCCN(CCOCCOC)CCOCCOC.Br[C:24]1[C:25](I)=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28].C[C:35]1[C:40](C)=[CH:39][CH:38]=[CH:37][C:36]=1[OH:42]>Cl[Cu]>[O:42]([C:25]1[CH:24]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:35]=1
Reactant: O=C(O)c1cccc(Br)c1I
Reactant: Cc1cccc(O)c1C
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Product: O=C(O)c1ccccc1Oc1ccccc1

Procedure:
As shown in the Scheme, at the presence of 10% by mole of CuCl and 10% by mole of tris(2-(2-methoxyethoxy)ethyl) amine (TDA-1), 3-bromo-2-iodo benzoic acid was contacted with 2,3-dimethylphenol to yield phenoxybenzoic acid. Without purification, the phenoxybenzoic acid was directly dehydrated and cyclized by reagents such as sulfuric acid, methanesulfonic acid, polyphosphoric acid, or polyphosphate to yield dimethylxanthone. Diethyl malonate was arylated by the dimethylxanthone under catalysis of palladium to yield 5,6-dimethylxanthone-4-ethyl acetate which was hydrolyzed to yield DMXAA.
Reaction SMILES: [CH:1]1([CH:4]2[CH2:8][CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:6]2[CH2:7][CH2:8][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5]2)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: C1CC(C2CC2)CN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a solution of 3-cyclopropylpyrrolidine (250 mg, 2.25 mmol) and DIEA (1.178 mL, 6.74 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (752 mg, 2.25 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 18 h before being cooled, concentrated, and charged (DCM) to a 40 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 745 mg (81%). 1H NMR (500 MHz, DMSO-d6) δ 5.05-5.00 (m, 1H), 3.25-3.19 (m, 2H), 3.15-3.11 (m, 1H), 2.94-2.90 (m, 1H), 2.62 (s, 3H), 2.36 (s, 3H), 2.06 (br. s., 1H), 1.73-1.69 (m, 2H), 1.29-1.27 (m, 6H), 0.72-0.69 (m, 1H), 0.45-0.40 (m, 2H), 0.16-0.10 (m, 2H). UPLC (M+H)=411.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:51][C:52]1[S:56][C:55]([CH:57]=[CH:58][C:59](O)=[O:60])=[CH:54][CH:53]=1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@H:17]([CH3:19])[N:16]([C:59](=[O:60])[CH:58]=[CH:57][C:55]4[S:56][C:52]([Cl:51])=[CH:53][CH:54]=4)[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1N[C@@H](C)CN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=C(O)C=Cc1ccc(Cl)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1C(=O)C=Cc1ccc(Cl)s1
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of (3S,5S)-1-(4-amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (42 mg, 0.147 mmol), major epimer from EXAMPLE 88, Part D, in 2 mL of DMF is added TBTU (52 mg, 0.162 mmol), triethylamine (0.02 mL, 0.162 mmol) and 3-(5-chloro-thiophen-2-yl)-acrylic acid (28 mg, 0.15 mmol), EXAMPLE 25. After stirring for two hours, the reaction mixture is directly purified by reverse phase HPLC (10-70% ACN/H2O). The product (35.5 mg, 36%) is isolated as a yellow solid with a melting point of 116-120° C. C22H22ClN5O2S: MS m/z: 456, 458. Anal. calcd. for C22H22ClN5O2S.C2HF3O2: C, 50.57; H, 4.07; N, 12.29. Found: C, 46.48; H, 3.64; N, 11.04.
Reaction SMILES: [CH2:1]([N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C>CS(C)=O>[NH2:20][C:18]1[N:19]=[C:14]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([N:3]([CH2:1][CH3:2])[CH3:12])=[O:5])[CH2:7]2)[CH:15]=[CH:16][C:17]=1[N+:21]([O-:23])=[O:22]
Reactant: CCN(C)C(=O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 80 °C
Yield: 49.3 %

Procedure:
To a solution of (R)—N-ethyl-N-methylpiperidine-3-carboxamide (600 mg, 4.1 mmol) in dimethylsulfoxide (6 mL) were added 6-chloro-3-nitropyridin-2-amine (0.58 g, 3.3 mmol) and triethylamine (1.2 mL, 8.3 mmol) at room temperature. The reaction mixture was heated to 80° C. for 18 h. The reaction mixture was poured into ice water, extracted with ethyl acetate and concentrated under reduced pressure. The crude material was purified via column chromatography (10% ethyl acetate in petroleum ether) to afford (R)-1-(6-amino-5-nitropyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (500 mg, 28.4%). MS (ES+) (M+H) 308.31.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH2:3]1.[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=3)[CH2:3]2)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(N2CC[C@@H](N)C2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 83.6 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-[(3R)-3-aminopyrrolidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (238a) (116 mg, 0.45 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (79 mg, 0.45 mmol), WSC hydrochloride (260 mg, 1.36 mmol), 1-hydroxybenzotriazole (61 mg, 0.45 mmol) and N-methylmorpholine (0.10 mL, 0.90 mmol), to obtain 155 mg of the title compound as a white solid (83%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]([CH2:11][P:12](=[O:15])([OH:14])[OH:13])[CH3:10])(=[O:8])=[O:7].[N+:16]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[NH4+:9].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([O:15][P:12]([CH2:11][N:9]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])[CH3:10])(=[O:13])[O-:14])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CN(CP(=O)(O)O)S(=O)(=O)c1cccs1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CN(CP(=O)([O-])Oc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1cccs1
Product: [NH4+]
Yield: 43 %

Procedure:
Compound (xi) was treated with 4-nitrophenol according to the procedure described in Example 1, step 4. The crude product was purified by flash chromatography (elution with chloroform:methanol:concentrated ammonium hydroxide; 8:2:0.25) to afford the ammonium salt 47 (43%) as a colorless solid: 1H NMR (400 MHz, CD3OD) δH 8.19-8.23 (m, 2H, Ar—H), 7.85 (dd, J=1, 5 Hz, 1H, Ar—H), 7.62 (dd, J=1, 4 Hz, 1H, Ar—H), 7.44 (dd, J=1, 9.5 Hz, 2H, Ar—H), 7.23 (dd, J=4, 5 Hz, 1H, Ar—H), 3.30 (d, J−13.5 Hz, 2H, NCH2P), 2.93 (s, 3H, NCH3); 13C NMR (100 MHz, CD3OD) δC 37.1, 47.4, 122.4 (d, J=4 Hz), 126.1, 128.9, 133.7 (d, J=7 Hz), 137.1, 144.7, 159.5; 31P NMR (162 MHz, CD3OD) δP 12.7; MS (neg. FAB) m/z 391 (M−1, 100%), 306 (15%), 153 (35%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8]O)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[OH2:28]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][C:21]1[CH:22]=[C:17]([CH3:27])[CH:18]=[CH:19][C:20]=1[S:23]([OH:28])(=[O:25])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCO
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOCCCc1cc(C)ccc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Butoxy propan-1-ol (3.15 g) synthesized in Reference Example 44 was dissolved in dichloromethane (80 mL), triethylamine (6.6 mL), p-toluenesulfonyl chloride (6.82 g) and 4-dimethylaminopyridine (0.29 g) were added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (4.46 g) as a colorless oil.
Reaction SMILES: C([Li])CCC.[N:6]1[C:11]2[NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[NH:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][C:25]#[CH:26]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[O:27]=[C:22]([N:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](=[O:17])[NH:16][C:10]2[CH:9]=[CH:8][CH:7]=[N:6][C:11]1=2)[CH2:23][CH2:24][C:25]#[CH:26]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: C#CCCC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCCC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
22.4 ml of a 1.6 molar solution of n-butyl-lithium in n-hexane are added dropwise with stirring, at 0° C., to a suspension of 3.7 g (0.017 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 150 ml of absolute tetrahydrofuran. After it has all been added, the mixture is stirred for a further 30 minutes and then mixed with a solution of 2.04 g (0.0175 mol) of 4-pentynoic acid chloride in 20 ml of tetrahydrofuran. The mixture is heated to 30° C. and stirred for a further hour. The reaction mixture is then poured into a saturated saline solution. The organic phase is diluted with ethyl acetate and, after being separated off, washed twice with saline solution, filtered over charcoal and evaporated to dryness in vacuo. The crude product is purified by column chromatography on silica gel using chloroform as eluant. 2.2 g (43% of theory) of colourless crystals were obtained, melting point 179°-180° C.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:4][N:3]=1.[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C1COCC1>[CH3:16][O:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[S:4][N:3]=1
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1nsc(Nc2ccccc2)c1C#N
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of 3-hydroxy-5-phenylamino-isothiazol-4-carbonitrile (2.82 g, 13 mmol), triphenylphosphine (4.04 g, 15.6 mmol), methanol (0.53 ml) in THF (25 ml) was added diethyl azadicarboxylate (DEAD, 2.46 ml, 15.6 mmol) at 0° C. The mixture was stirred at ambient temperature and evaporated to give a residue. The crude product was purified on silica gel (hexane/EtOAc, 1:1) to give a yellow powder (1.26 g, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)[CH2:13][CH2:12][N:11]([CH3:30])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2(COCc3cc(C(F)(F)F)cc4cn[nH]c34)CCNCC2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-(4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indazole (50 mg, 0.123 mmol) and sodium cyanoborohydride (7.7 mg, 0.123 mmol) in acetonitrile (1 mL) at room temperature was added formalin (25 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. The product was purified by preparative HPLC. The trifluoroacetic acid salt was loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 28 mg (54%). 1H-NMR (CDCl3, 500 MHz) δ 9.81 (bs, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.33 (m, 2H), 7.26 (s, 1H), 7.12 (m, 2H), 4.73 (s, 2H), 3.54 (s, 2H), 2.55 (m, 2H), 2.22 (m, 7H), 1.96 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 162.6, 160.6, 139.6, 135.4, 128.7, 128.6, 124.7 (q, J=272 Hz), 123.3 (q, J=32 Hz), 122.9, 121.8, 120.3 (q, J=2.9 Hz), 118.4 (q, J=4.8 Hz), 115.8, 115.6, 80.4, 71.9, 51.8, 46.3, 40.3, 32.9. Mass spec.: 422.13 (MH)+. Accurate mass spec.: m/z 422.1836 [MH]+, Δ=4.6 ppm.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([CH3:34])[CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:30]1([CH2:29][O:28][C:20]2[CH:21]=[CH:22][C:23]([CH:25]([F:27])[F:26])=[CH:24][C:19]=2[C:18]2[C:13]3[NH:12][C:11]([CH3:33])=[C:10]([C:8]([NH:7][C@@H:5]4[CH2:6][C@@H:2]([NH:1][C:35](=[O:38])[CH2:36][CH3:37])[CH2:3][C@H:4]4[CH3:34])=[O:9])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:32][CH2:31]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1C
Reactant: CCC(=O)Cl
Product: CCC(=O)N[C@H]1C[C@@H](C)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4S*)-4-amino-2-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f69) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]3[O:15][C:16](=[O:18])[CH:17]=[C:10]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26]N1C(=O)CCC1=O>C(#N)C>[Cl:26][C:17]1[C:16](=[O:18])[O:15][CH:11]2[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1C=C2C(CCCN2Cc2ccc(Cl)nc2)O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1OC2CCCN(Cc3ccc(Cl)nc3)C2=C1Cl
Reaction time: 1 h
Yield: 72.6 %

Procedure:
524 mg (1.98 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one (1-2) are dissolved in 20 ml of acetonitrile, then 414 μl (2.97 mmol) of triethylamine and 317 mg (2.37 mmol) of N-chlorosuccinimide are added at room temperature. After one hour of stirring, a 159 mg (1.19 mmol) of N-chlorosuccinimide are added. After a further hour of stirring, the entire reaction mixture is concentrated under reduced pressure. The residue is taken up in dichloromethane, washed successively twice with 1N aqueous hydrochloric acid, twice with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 430 mg (72% of theory) of 3-chloro-4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:30])=[CH:4][C:5]([Cl:29])=[C:6]([C:8]2[C:9](=[O:28])[N:10]([CH2:26][CH3:27])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[Cl:29][C:5]1[C:6]([C:8]2[C:9](=[O:28])[N:10]([CH2:26][CH3:27])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[C:3]([F:30])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)CC3)cc21
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC3CCN(C)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpiperidin-4-ylamino)-1,6-naphthyridin-2(1H)-one (200 mg, 0.465 mmol) and pyridine (70 mg, 0.95 mmol) in DCM (5 mL) was treated drop-wise with phenyl isocyanate (112 mg, 0.93 mmol) and stirred at RT under nitrogen overnight. The mixture was quenched with MeOH (5 mL), concentrated under reduced pressure and purified by prep-TLC separation to give 1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (120 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.72 (s, 1H), 8.39 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.51 (d, J=10.8 Hz, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.26 (t, J=8.0 Hz, 2H), 7.02-6.94 (m, 2H), 6.33 (s, 1H), 4.11-4.05 (m, 2H), 3.81-3.78 (m, 1H), 2.78-2.75 (m, 2H), 2.20 (s, 3H), 2.12-2.05 (m, 2H), 1.90-1.88 (m, 2H), 1.52-1.47 (m, 2H), 1.21-1.18 (m, 3H); MS (ESI) m/z: 549.3 [M+H]+.
Reaction SMILES: O.O.O.[CH2:4]([N:6]([CH2:10][CH3:11])[C:7](=[S:9])[S-:8])[CH3:5].[Na+].[CH:13]([C:15]1[CH:22]=[CH:21][C:18](CCl)=[CH:17][CH:16]=1)=[CH2:14].O>C(O)C>[CH:13]([C:15]1[CH:22]=[CH:21][C:18]([S:9][C:7](=[S:8])[N:6]([CH2:10][CH3:11])[CH2:4][CH3:5])=[CH:17][CH:16]=1)=[CH2:14]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=Cc1ccc(SC(=S)N(CC)CC)cc1
Reaction time: 0.5 h

Procedure:
A solution of sodium diethyldithiocarbamate trihydrate (3.5 g, 1.55×10−2 mol) in 20 mL of ethanol was added to a flask equipped with a stirrer, dropping funnel and a reflux condenser. To this solution was added a solution of 4-vinylbenzyl chloride (3.0 g, 1.96×10−2 mol) and ethanol (5 mL), dropwise, over a period of 0.5 h at a temperature of 0° C. The resultant solution was stirred at room temperature for 24 h before pouring into a large volume of water and extracting with diethyl ether. The ether phase was washed three times with water, dried over sodium sulphate, before finally removing the diethyl ether by evaporation. The residue was recrystallised three times from methanol, giving a yield of 2.6 grams (83%). 1H NMR (CDCl3) δ7.36 (s, 4H, C6H4), 6.70 (dd, J=11.6 and 17.5 Hz, 1H, CH═CH2), 5.73 (d, J=17.5 Hz, 1H, CH═CH2), 5.24 (d, J=11.5 Hz, 1H, CH═CH2), 4.54 (s, 2H, CH2S), 4.04 (q, J=7.3 Hz, 2H, NCH2), 3.73 (q, J=6.6 Hz, 2H NCH2), 1.19 (t, J=ca. 7.0 Hz, 6H CH2CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]2)=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+]>CO.[Pd].O>[F:23][C:20]([F:21])([F:22])[C:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[N:12]=1
Reactant: O=[N+]([O-])c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A solution of 1-[(4-nitrophenyl)methyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (410 mg, 1.26 mmol) in methanol (3 ml) was added dropwise to a stirred suspension of 10% palladium on charcoal in water (1.3 ml) containing sodium borohydride (95 mg, 2.50 mmol), under argon with cooling. The resulting mix was stirred at room temperature for 1 hour. The reaction mix was filtered and then acidified using 2M HCl to destroy any excess sodium borohydride, and then basified again using 2M aqueous sodium hydroxide. The mix was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give a yellow oil, which was chromatographed on a 5 g pre-packed silica column eluting from 0-20% ethyl acetate in petroleum ether to give the title compound as a yellow oil (166 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.CN1CCOCC1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:33])([F:24])[F:34])=[CH:31][N:30]=3)=[O:16])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.088 g, 0.370 mmol; Example 216A) in dichloromethane (1 mL) was added oxalyl dichloride (0.308 mL, 0.617 mmol). After 30 minutes, the reaction was concentrated and dried. This residue was dissolved in dichloromethane (1 mL) and 5-(trifluoromethyl)pyridin-2-amine (0.050 g, 0.308 mmol) was added followed by 4-methylmorpholine (0.068 mL, 0.617 mmol). After stirring for 30 minutes, the reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.57-8.52 (m, 1H), 8.28 (d, J=8.7, 1H), 7.92 (dd, J=2.3, 8.8, 1H), 7.35-7.21 (m, 2H), 7.09-6.99 (m, 2H), 4.25 (d, J=16.0, 1H), 4.18 (d, J=16.0, 1H), 3.78 (t, J=9.0, 1H), 3.69-3.59 (m, 2H), 2.63 (m, 1H), 2.23 (m, 1H); MS (ESI+) m/z 382.0 (M+H)+.