Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[N:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)[N:25]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-(5-Chloro-1H-indol-3-yl)ethanamine hydrochloride (0.044 g; 0.187 mmol), 6-(3-fluorobenzyl)picolinic acid (0.045 g; 0.196 mmol), HATU (0.073 g; 0.192 mmol) and N,N-diisopropylethylamine (0.082 mL; 0.466 mmol) in DMF (3 mL) was stirred overnight at room temperature and was concentrated in vacuo. The residue was dissolved in dichloromethane and the organic layer was washed three times with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% of ethyl acetate in dichloromethane) to give 0.053 g (70%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-(3-fluorobenzyl)picolinamide as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][OH:13].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:7][CH2:8][CH2:9][N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][OH:13]
Reactant: ClCc1ccccc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OCCN(CCO)Cc1ccccc1

Procedure:
The improvements in the above process aspects of the invention which afford a substantially quantitative yield of N,N-bis(2-chloroethyl)benzylamine, are based in part on modifications which eliminate formation of by-products and in part on a reverse in the order of addition of reactants. One improvement is based on the use of a molar equivalent quantity of sodium carbonate in the reaction of bis(2-hydroxyethyl)amine with benzyl chloride to produce N,N-bis(2-hydroxyethyl)benzyl amine, thereby completely inhibiting formation of the by-products N,N-dibenzyl-N-(2-hydroxyethyl)amine and N-benzyl-N-(2-benzyloxyethyl)-N-(2-hydroxyethyl)amine, which are produced in relatively large quantities (about 16% and 20% respectively) in the absence of said sodium carbonate. Another improvement is based on the addition of N,N-bis(2-hydroxyethyl)benzylamine in toluene solution to slightly more than a two molar excess of thionyl chloride rather than the heretofore reverse addition of thionyl chloride to N,N-bis(2-hydroxyethyl)benzylamine, thereby completely eliminating the formation of N-benzylmorpholine. Another improvement is the azeotropic distillation of the toluene solution of N,N-bis(2-hydroxyethyl)benzylamine to remove the water formed by the reaction, thereby avoiding the use of excess thionyl chloride to ensure completion of reaction in the chlorination step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:38][CH:37]2[CH2:39][CH:33]([CH2:34][CH2:35][CH2:36]2)[CH2:32]1>>[CH:37]12[CH2:39][CH:33]([CH2:34][CH2:35][CH2:36]1)[CH2:32][N:31]([CH2:30][CH2:29][N:14]1[CH2:15][CH2:16][C:11]3[C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]1)[CH2:38]2
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: ClCCN1CC2CCCC(C2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CC2CCCC(C2)C1)C3
Reaction time: 96 h
Yield: 63.9 %

Procedure:
Prepared by the method described for Example 13 from 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.011 moles), triethylamine (6.4 ml, 0.046 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.3.1]nonane hydrochloride (3.0 g, 0.013 moles). The reflux time is 96 hours. Recrystallization from ethanol gave the product (2.9 g), mp 122°-125° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:12]([CH:18]([CH3:20])[CH3:19])[C:13](OCC)=[O:14]>>[NH:7]([C:8]1[S:9][CH:12]([CH:18]([CH3:20])[CH3:19])[C:13](=[O:14])[N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: NC(=S)Nc1ccccc1
Product: CC(C)C1SC(Nc2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-phenylthiourea and ethyl 2-bromo-3-methylbutanoate according to Method C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1([C:12]2[C:21]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[C:15]([O:22][CH3:23])=[CH:14][CH:13]=2)[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)#[N:4].[OH2:24]>C1COCC1>[C:3]([C:5]1([C:12]2[C:21]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[C:15]([O:22][CH3:23])=[CH:14][CH:13]=2)[CH2:6][CH2:7][C:8](=[CH:15][C:16]([O:17][CH2:18][CH3:19])=[O:24])[CH2:9][CH2:10]1)#[N:4]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1OCCO2
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of triethyl phosphonoacetate (0.72 mL, 3.6 mmol) in THF (9.4 mL) was added 60% sodium hydride (0.15 g, 3.6 mmol) under ice-cooling. The mixture was stirred at room temperature for 15 minutes, Compound 1 (0.94 g, 3.3 mmol) obtained in Example 1 was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, water was added under ice-cooling, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=2/1) to give Compound 10 (1.4 g, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([Cl:18])=[C:12]([F:19])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([Cl:18])=[C:12]([F:19])[C:3]=1[C:4]([C:6](=[CH:20][O:21][CH2:22][CH3:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1c(F)c(Cl)c(F)c(F)c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(Cl)c(F)c(F)c1Cl
Temperature: 150 °C

Procedure:
A mixture of 31.5 g (0.1 mol) of ethyl (2,5-dichloro-3,4,6-trifluorobenzoyl)-acetate, 22.2 g (0.15 mol) of triethyl orthoformate and 25.5 g (0.25 mol) of acetic anhydride is heated under reflux for 2 hours (heating bath temperature of 150° C.). Low-boiling constituents are distilled off first under a waterpump vacuum and then under a high vacuum up to a bottom temperature of 130° C. The residue is used further as crude product.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>P(Cl)(Cl)(Cl)=O>[CH:2]([C:3]1[O:20][C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:21])[CH3:1]
Reactant: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(C)cc2)oc1C(C)C

Procedure:
13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate in 80 ml of phosphorus oxychloride are heated to the boil under reflux for 2 h. The phosphorus oxychloride is removed under reduced pressure and the resulting residue is dissolved in 200 ml of dichloromethane, washed three times with saturated NaHCO3 solution and dried over MgSO4, and the solvent is then removed under reduced pressure. This gives 11 g of ethyl 5-isopropyl-2-p-tolyloxazole-4-carboxylate as a brownish sold. C16H19NO3 (273.33), MS (ESI)=292 (M+H+), Rf(n-heptane:ethyl acetate)=2:1)=0.43.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[CH3:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:29]
Reactant: CC(C)CCCC(=O)O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 63 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 5-methylhexanoic acid (3.9 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g), and after recrystallization in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (8 g), m.p. 132° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH3:9])[C:6](=[S:19])[NH:5][C:4](=[O:20])[CH:3]=1.[N:21]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:21][C:3]1[C:4](=[O:20])[NH:5][C:6](=[S:19])[N:7]([CH:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH3:9])[C:2]=1[NH2:1]
Reactant: CC(c1nc2ccccc2[nH]1)n1c(N)cc(=O)[nH]c1=S
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(c1nc2ccccc2[nH]1)n1c(N)c(N)c(=O)[nH]c1=S
Reaction time: 0.33 h

Procedure:
To 6-amino-1-[1-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.21 g, 0.74 mmol, obtained from Example 9(d)) in acetic acid (2 mL) was added, dropwise, a solution of sodium nitrite (0.056 g, 0.81 mmol) in H2O (0.5 mL). After 50 minutes sodium dithionite (0.26 g, 1.5 mmol) was added and the reaction was stirred 20 minutes, followed by evaporation of acetic acid in vacuo and addition of water (25 mL). The precipitated solid was collected by filtration, washed with H2O and dried giving the title compound, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:33](=[O:42])[C:32]=1[C:43]#[N:44]>O1CCOCC1.CCOC(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>[Cl:1][C:2]1[CH:14]=[C:13]([C:31]2[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[C:33](=[O:42])[C:32]=2[C:43]#[N:44])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: N#Cc1c(Br)ccn(CCC2CC2)c1=O
Reactant: CC1(C)OB(c2ccc(OC3CCOCC3)c(Cl)c2)OC1(C)C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(OC3CCOCC3)c(Cl)c2)ccn(CCC2CC2)c1=O
Yield: 15.9 %

Procedure:
To a solution of intermediate 18 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 9 (0.45 g, 1.7 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 4 (0.108 g, 17%).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1>>[N:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)[CH:27]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Reactant: Brc1ccc2cccnc2c1
Product: c1cnc2cc(-n3c4c(c5ccccc53)CN3CCC4CC3)ccc2c1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 7-bromoquinoline (312 mg, 1.5 mmol; Ark Pharm) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.96-2.23 (m, 4H) 2.99-3.05 (m, 1H) 3.10-3.30 (m, 4H) 4.37 (s, 2H) 7.07-7.21 (m, 3H) 7.40-7.49 (m, 1H) 7.59-7.69 (m, 2H) 7.97 (d, J=2 Hz, 1H) 8.17 (d, J=9 Hz, 1H) 8.50 (d, J=7 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8].Cl.[C:18](=N)(OC)[CH3:19]>C(OCC)C>[CH3:18][C:19]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=2[N:3]=1
Reactant: CCCNc1ccc(C(=O)O)cc1N
Reactant: COC(C)=N
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCCn1c(C)nc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 116.5 %

Procedure:
To a methanol (17 mL) solution of 3-amino-4-n-propylaminobenzoic acid (see Working Example 82-2) (1.68 g, 8.65 mmol) was added methyl acetimidate hydrochloride (1.14 g, 10.4 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, diethyl ether was added, and this was allowed to stand at room temperature for 10 minutes. The crystals obtained were filtered, and after being washed with diethyl ether, they were dried to yield the title compound (2.20 g, quant.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](Cl)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:35])[CH2:33][CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:42]5[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:32](=[O:35])[CH2:33][CH3:34])=[CH:16][N:15]=2)[CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 82.1 %

Procedure:
Following general procedure II, (S)-tert-butyl(1-(5-((6-chloro-3-prop ionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (83 mg, 0.31 mmol) to afford the product (102 mg) which was carried forward without any purification: ESI MS m/z 621 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:35]([O:36][CH3:37])=[CH:34][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C@@H:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:35]([O:36][CH3:37])=[CH:34][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C@@H:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(C[C@H](C)O)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(C[C@H](C)O)CC2
Yield: 70 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and (S)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. The product was isolated as an off-white foam (72 mg, 70%). MS: 513 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 6.33 (s, 2H), 5.60 (s, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 4H), 3.08 (s, 1H), 2.88 (m, 8H), 2.62 (br s, 2H), 2.53 (m, 2H), 2.27 (m, 2H), 1.66 (d, J=8.5 Hz, 1H), 1.16 (d, J=6 Hz, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([O:38][C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[NH:46][C:47]2[C:48]3[C:55]([CH3:56])=[C:54]([C:57](O)=[O:58])[S:53][C:49]=3[N:50]=[CH:51][N:52]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.[CH3:69][N:70]1[CH:74]=[CH:73][C:72]([NH2:75])=[N:71]1>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([O:38][C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[NH:46][C:47]2[C:48]3[C:55]([CH3:56])=[C:54]([C:57](=[O:58])[NH:75][C:72]4[CH:73]=[CH:74][N:70]([CH3:69])[N:71]=4)[S:53][C:49]=3[N:50]=[CH:51][N:52]=2)[CH2:33]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Reactant: Cn1ccc(N)n1
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
Product: Cc1c(C(=O)Nc2ccn(C)n2)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU was added into a solution of 4-[2-((S)-1-tert-Butoxycarbonyl-piperidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (100 mg) and DIPEA in anhydrous DMF (2 ml) at 0° C. The reaction was stirred for 0.5 h when 1-methyl-1H-pyrazol-3-amine (100 μl) was added and the reaction allowed to warm to room temperature and stirred for 2 h. The DMF was removed by co-evaporation from toluene and the residue was purified by chromatography to give the intended product.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:24][S:25](O)(=[O:27])=[O:26]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=[C:9]([S:25]([Cl:24])(=[O:27])=[O:26])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)c1cc2cccc(OCc3ccc([N+](=O)[O-])cc3)c2o1
Product: CC(=O)c1cc2c(S(=O)(=O)Cl)ccc(OCc3ccc([N+](=O)[O-])cc3)c2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Acetyl-7-p-nitrobenzyloxybenzofuran (3 g) was added to chlorosulfonic acid at -15° C. for 30 minutes. After the reaction mixture was stirred at -10° to -5° C. for 1 hour, the resultant was gradually added dropwise to ice-water. The solution was extracted with ethyl acetate, washed with water and dried, ethyl acetate being distilled away under reduced pressure to give 2.7 g of crude 2-acetyl-4-chlorosulfonyl-7-p-nitrobenzyloxybenzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:30][CH3:31])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([CH3:26])=[C:24]([CH:27]=O)[NH:23][C:22]=1[CH3:29])=[O:20])[CH3:13]>>[CH2:30]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[C:25]([CH3:26])=[C:24]([CH:27]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:23][C:22]=1[CH3:29])=[O:20])[CH3:31]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C
Yield: 97.2 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.5 g, 2.36 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylaminopropyl)amide (0.51 g) to give 0.84 g of the title compound as a red-orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[O:10])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3cccc(Cl)c3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 3-chlorophenyl isocyanate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 5. Analytic LCMS (M+H)+: m/z=478.3/480.3.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[C:19]2[N:18]=C(C)O[C:15](=[O:21])[C:14]=2[CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1.O1CCCC1>[NH2:18][C:19]1[C:10]([Cl:9])=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1nc2c(Cl)cccc2c(=O)o1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Nc1c(Cl)cccc1C(=O)c1ccccc1
Yield: 38.8 %

Procedure:
Phenylmagnesium bromide (3.11 mL, 3.0 M in ether, 9.34 mmol) was added at room temperature to a solution of 8-chloro-2-methyl-4H-3,1-benzoxazin-4-one (2.15 g, 10.9 mmol) in benzene (10 mL) and tetrahydrofuran (3 mL). The reaction was refluxed for 2h, cooled, and quenched with 2N hydrochloric acid (10 mL). The layers were separated and the organic phase washed with 5% sodium hydroxide, dried over magnesium sulfate, and concentrated. The residue was refluxed in ethanol (12 mL) and 6N hydrochloric acid (6 mL) overnight, then concentrated in vacuo. The residue was dissolved in benzene (30 mL) and treated with 5N ammonium hydroxide (20 mL). The organic extract was dried and concentrated. The crude product was purified by chromatography (silica gel, 0 to 5% ethyl acetate in hexane gradient elution), giving the title compound (0.84 g). 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J=7 Hz, 2H), 7.54 (t, J=7 Hz, 1H), 7.49–7.42 (m, 3H), 7.39 (d, J=8 Hz, 1H), 6.56 (t, J=8 Hz, 1H), 6.58 (br s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8]([NH2:12])=[C:9]([Cl:11])[CH:10]=1)=[O:4].[OH-].[Na+].O>CO>[NH2:12][C:8]1[N:7]=[C:6]([O:13][CH3:14])[C:5]([C:3]([OH:4])=[O:2])=[CH:10][C:9]=1[Cl:11]
Reactant: COC(=O)c1cc(Cl)c(N)nc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1nc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C

Procedure:
A solution of methyl-6-amino-5-chloro-2-methoxypyridine-3-carboxylate (0.32 g) in MeOH (5 mL) was treated with 2.5N NaOH (0.6 mL) and H2O (5 mL) and the reaction stirred at room temperature until the reaction was complete by TLC. The MeOH was removed by rotary evaporation and the residue carefully acidified with 5N HCl to give the title compound which was collected and dried (0.15 g).