Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[C:8]([N+:15]([O-])=O)[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH:6]=[CH:5]1)([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[CH:1]([N:4]1[C:12]2[C:7](=[C:8]([NH2:15])[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])c2ccn(C(C)C)c12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N)c2ccn(C(C)C)c12

Procedure:
A solution of 1-isopropyl-7-methoxy-4-nitro-1H-indole (T) (1 eq) and palladium 10% on activated carbon (0.1 wt eq) in methanol/ethyl acetate (1:1) was shaken on a Parr hydrogenation apparatus under hydrogen for 1 hr. The reaction was then filtered through Celite and evaporated to dryness to produce the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[C:6]=1[NH2:7]
Reactant: Nc1[nH]ncc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 4-bromo-1H-pyrazol-5-amine (1 g, 6.17 mmol) in THF (20 mL) at 0° C. was added NaH (0.494 g, 12.35 mmol) and stirred at the same temperature for 30 mins To this mixture was then added SEM-Cl (1.095 mL, 6.17 mmol) and slowly allowed to raise to rt and stirred at rt for 1 h. The reaction mix was then quenched with Satd. NH4Cl and then extracted with EtOAc, dried over Na2SO4, filtered, and concentrated. Purification by normal phase chromatography afforded 221A (1.45 g, 80% yield) as a pale yellow oil. MS (ESI) m/z: 292.0 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:25])=[O:24])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[Cl-].[NH4+]>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:24])=[O:25])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCC1(C)NS(=O)(=O)N(Cc2ccccc2)C1=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCC1(C)C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
Potassium t-butoxide (3.93 g, 35.06 mmol) was added in one portion to a solution of 2-phenylmethyl-4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9 g, 31.87 mmol) in 250 ml of THF at 0° C. and the mixture was stirred under nitrogen at this temperature for 1 hour. To the mixture was added methyl iodide (27.14 g, 191.22 mmol) at 0° C. and the resulting mixture was allowed to stir at 0° C. for 1/2 hour and at room temperature for 11 hours. The resulting mixture was poured into 400 ml of saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo to afford 9.28 g (98%) of 2-phenylmethyl-4-methyl-4 -propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =propyl; R2 =CH3 ; R3 =methyl ) as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[C:31]2[CH:38]=[CH:37][NH:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:33]1[C:32]2[NH:36][CH:37]=[CH:38][C:31]=2[C:30]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])=[CH:17][CH:16]=3)[C:13](=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:28])[N:6]=2)[CH2:3][CH3:4])=[N:35][CH:34]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 13.4 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(4-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (35 mg, 0.089 mmol, 1.0 equiv) in t-BuOH (0.09 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (16 mg, 0.11 mmol, 1.2 equiv) and diisopropylethylamine (31 μL, 0.18 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 6.1 mg of the title compound (13% yield).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1cc2c(Cl)cccc2c(N2CCSCC2)n1
Agent: Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: Clc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 97 %

Procedure:
1-Thiomorpholino-3-piperazino-5-chloro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3,5-dichloro-isoquinoline and piperazine by heating in diphenyl ether at 200°C. M.p. of its hydrochloride: 273°-275°C (from water); yield: 97% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=1[C:23]([F:26])([F:25])[F:24]>>[CH:19]([C:18]1[CH:21]=[CH:22][C:15]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=2)[C:5]#[N:6])=[C:16]([C:23]([F:24])([F:25])[F:26])[CH:17]=1)=[O:20]
Reactant: N#Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: N#Cc1cc(Oc2ccc(C=O)cc2C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-hydroxy-5-(trifluoromethyl)benzonitrile and 4-fluoro-3-(trifluoromethyl)benzaldehyde.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Br:48][C:49]1[CH:50]=[CH:51][C:52]([NH:58][CH3:59])=[C:53]([CH:57]=1)[C:54](O)=[O:55].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[C:49]([Br:48])[CH:50]=[CH:51][C:52]=3[NH:58][CH3:59])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CNc1ccc(Br)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1ccc(Br)cc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 5-bromo-2-methylaminobenzoic acid (8.4 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)C1CCCN1
Yield: 76.7 %

Procedure:
A solution of 3-(3-pyridyl)-1-propyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.0 g; 8.9 mmol) in methylene chloride (40 mL) and trifluoroacetic acid (8 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3×). The combined organic extracts were dried and concentrated to yield 1.60 g (77%) of the free amine as a thick oil, 1H NMR (300 MHz, CDCl3): δ 1.71-2.09 (m, 6H); 2.63 (m, 2H); 2.86 (m, 1H); 2.94 (m, 1H); 3.71 (m, 1H); 4.11 (m, 2H); 7.18 (m, 1H); 7.45 (m, 1H); 8.41 (m, 2H).
Reaction SMILES: [N:1]#[N:2].O.Cl.Cl.C[O:7][C:8](=[O:34])[C@H:9]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])[NH:10][S:11]([C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:19]([N:20]([CH3:22])[CH3:21])[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:35]([NH2:37])[CH3:36]>O1CCCC1>[N:1]#[N:2].[OH2:7].[S:11]([NH:10][C@H:9]([C:8]([NH:37][CH2:35][CH3:36])=[O:34])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])([C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:19]([N:20]([CH3:21])[CH3:22])[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: CCN
Reactant: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Agent: Cl
Agent: N#N
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 72 h
Yield: 93 %

Procedure:
To a suspension of 1.0 gram of N2 -dansyl-L-arginine methyl ester dihydrochloride monohydrate in 1 ml of tetrahydrofuran was added 3 ml of ethylamine with cooling. The mixture was allowed to stand in a sealed tube at room temperature for three days. After the excess amine was removed by evaporation, the residue was poured into 50 ml of water to give a precipitate. Recrystallization from 50% aqueous methanol afforded N2 -dansyl-N-ethyl-L-argininamide monohydrate in 93% yield; mp. 220°-222° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([CH2:18][P:19]([O:25]C(C)C)([O:21]C(C)C)=[O:20])=[CH:8][C@@H:9]([NH:15]C=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.C(Cl)Cl.C[Si](C)(C)Br>C(O)C>[NH2:15][C@H:9]([CH:8]=[C:7]([CH2:18][P:19]([OH:25])([OH:21])=[O:20])[CH2:6][CH2:5][OH:4])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)[C@@H](C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)[C@H](N)C=C(CCO)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
12.7 g (30.2 mmol) of ethyl 6-acetoxy-2(R)-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate are dissolved in 100 ml of abs. CH2Cl2 and 15.6 ml (120.8 mmol) of trimethylbromosilane are added to this solution at room temperature. The reaction mixture is allowed to stand for 24 hours at room temperature. After addition of 100 ml of abs. ethanol the reaction mixture is again allowed to stand for 24 hours at room temperature and then concentrated by evaporation. The residue is dissolved in ethanol and then a mixture of 100 ml of propylene oxide and 100 ml of ethanol is added dropwise. The suspension so obtained is stirred for 1 hour at 0° C. and then filtered with suction. The filter product is stirred overnight in ether and again filtered with suction. The filter product is dried, giving white crystals of ethyl 2(R)-amino-6-hydroxy-4-phosphonomethyl-hex-3-enoate. Melting point: 170° C. (decomp.). ee=92%; αD =-45.6°± 1° (c=1.0 H2O).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].Br[CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([CH2:13][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH2:15][CH2:16]1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC1(F)CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
1.2 g of 2-(3,3,3-trifluoropropyl)malononitrile and 0.76 g of 4-bromomethyl-1,1-difluorocyclohexane were dissolved in 10 ml of N,N-dimethylformamide, 0.99 g of potassium carbonate was added, and the mixture was stirred at room temperature overnight. Thereafter, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.51 g of 2-(4,4-difluorocyclohexyl)methyl-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (83)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([CH:15]1[CH2:17][O:16]1)([CH3:14])([CH3:13])[CH3:12]>>[CH3:12][C:11]([CH3:14])([CH3:13])[CH:15]([OH:16])[CH2:17][O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8]
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)(C)C1CO1
Product: CC(C)(C)C(O)COc1c(Cl)nc(Cl)nc1Cl
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of 2,4,6-trichloro-pyrimidin-5-ol (400 mg, 2.01 mmol) and 2-tert-butyl oxirane (3 mL) was heated at 100° C. for 3 hours before being cooled and concentrated in vacuo. The resultant residue was triturated in hot methanol and the insoluble material removed. The filtrate was concentrated in vacuo and the resultant residue was purified by column chromatography (SiO2, 0-15% ethyl acetate in cyclohexane) to give 3,3-Dimethyl-1-(2,4,6-trichloro-pyrimidin-5-yloxy)-butan-2-ol as a white solid (275 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 4.28 (1H, dd, J=9.38, 2.19 Hz), 4.00 (1H, t, J=9.19 Hz), 3.76-3.69 (1H, m), 2.53 (1H, d, J=3.48 Hz), 0.95 (9H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[C:24]4[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][C:16]=3[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:30])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40]>C(Cl)Cl>[CH2:39]([N:41]([CH2:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[C:24]4[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][C:16]=3[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:30])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH2:42][CH3:43])[CH3:40]
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(CCl)cc2)c1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A solution of {4-[3-(4-chloromethyl-benzyloxy)-phenyl]-8-trifluoromethyl-quinolin-3-yl}phenyl-methanone (011 g, 0.2 mmol) and diethylamine(0.3 g, 5.7 mmol) in CH2Cl2 (5 ml) was stirred at r.t. After 24 hr, the reaction was concentrated and purified by column chromatography (eluent 25% EtOAc/Hex) to give the title compound as a foam (0.10 g); MS m/z 569.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:35])=[C:7]([C:24]([NH:26][CH2:27][CH:28]([CH2:30][CH:31]([OH:34])[CH2:32][OH:33])[OH:29])=[O:25])[C:8]([I:23])=[C:9]([C:21]=1[I:22])[C:10]([NH:12][CH2:13][CH:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[OH:15])=[O:11])(=[O:3])[CH3:2].Cl[CH2:37][CH2:38][OH:39].OS(O)(=O)=O>[OH-].[Na+]>[OH:34][CH:31]([CH2:32][OH:33])[CH2:30][CH:28]([OH:29])[CH2:27][NH:26][C:24](=[O:25])[C:7]1[C:6]([I:35])=[C:5]([N:4]([CH2:37][CH2:38][OH:39])[C:1](=[O:3])[CH3:2])[C:21]([I:22])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[OH:15])=[O:11])[C:8]=1[I:23]
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Reactant: OCCCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(CCO)c1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Acetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide, prepared as in Example 2, Step B, (83.5 g, 0.1 g-mole) is dissolved in 1 N NaOH (140 ml, 0.14 g-mole) and the solution is stirred at room temperature for 1 hour and 2-chloroethanol (13.7 g, 0.17 g-mole) is added. The solution is stirred at 50° C. for 5 hours to complete the reaction. The solution is acidified with H2SO4 and evaporated to dryness under reduced pressure. The residue is triturated with MeOH and the precipitated solid is filtered. The mother liquor is concentrated under vacuum and the crude product is purified by reverse-phase (C18) HPLC to give the purified final product. The yield of this reaction and purification is 80%.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([C:36]3[NH:37][CH:38]=[CH:39][N:40]=3)[CH2:22][C:23]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:25](=[CH:26][N:27]([CH2:33][O:34][CH3:35])[N:28]=4)[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:45]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C@@H:21]([C:36]3[N:37]([CH2:45][C:44]4[CH:43]=[C:42]([F:41])[CH:49]=[C:48]([F:50])[CH:47]=4)[CH:38]=[CH:39][N:40]=3)[CH2:22][C:23]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:25](=[CH:26][N:27]([CH2:33][O:34][CH3:35])[N:28]=4)[CH:24]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COCn1cc2cc(CC(OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)c3ncc[nH]3)cc(C)c2n1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCn1cc2cc(C[C@@H](OC(=O)N3CCC(c4cc5ccccc5[nH]c4=O)CC3)c3nccn3Cc3cc(F)cc(F)c3)cc(C)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(1H-Imidazol-2-yl)-2-(2-(methoxymethyl)-7-methyl-2H-indazol-5-yl)ethyl 4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (102 mg, 0.19 mmol), 3,5-difluorobenzyl bromide (27.0 μL, 0.21 mmol, 1.1 equiv), and potassium carbonate (54 mg, 3.0 equiv) were combined in dimethylformamide (2.0 mL). After stirring at room temperature for 16 h, the reaction mixture was removed in vacuo and the residue purified by column chromatography to afford 72.0 mg (57%). Mass spec.: 667.4 (MH)+.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)=[O:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCOc1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOc1ccc(OCC(=O)n2n[n+]([O-])c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a suspension of 1-hydroxybenzotriazole (0.53 g) and 2-(4-octyloxyphenoxy)acetic acid (1 g) in dichloromethane (30 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (0.886 g), and stirred for 3 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[2-(4-octyloxyphenoxy)acetyl]benzotriazole 3-oxide (892 mg). To a solution of The Starting Compound (1.79 g) and 1-[2-(4-octyloxyphenoxy]benzotriazole 3-oxide (892 mg) in N,N-dimethylformamide (18 ml) was added 4-(N,N-dimethylamino)pyridine (0.297 g), and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The powder was added to water, and subjected to ion-exchange column chromatography on DOWEX-50WX4, and eluted with water. The fractions containing the object compound were combined, and subjected to column chromatograph on ODS (YMC-gel.ODS-AM.S-50), and eluted with 50% methanol aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove methanol. The residue was lyophilized to give The Object Compound (24) (1.75 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:6]([O:27][CH3:28])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[C:17]([C:24](=[O:26])[CH3:25])[CH:18]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Oc2ccnc3cc(OCCCl)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OCCN4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
1-(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone (compound 119) (89 mg), morpholine (57 mg), and potassium carbonate (152 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (24 mg, yield 24%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]2[CH2:25][CH2:24]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.Br[CH2:34][C:35]#[N:36].CCN(C(C)C)C(C)C>>[CH2:26]([N:22]([CH:23]1[CH2:25][CH2:24]1)[CH2:21][CH2:20][CH2:19][CH2:18][N:10]([CH2:9][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][CH2:34][C:35]#[N:36])[CH:8]=[CH:7][N:6]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(CCCCN(Cc1ccccc1)C1CC1)Cc1cc(CN)ccn1
Reactant: N#CCBr
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCCCN(Cc1ccccc1)C1CC1)Cc1cc(CNCC#N)ccn1

Procedure:
By General Procedure T from tert-butyl N-{[4-(aminomethyl)pyridin-2-yl]methyl}-N-{4-[benzyl(cyclopropyl)amino]butyl}carbamate (1 equiv.) and bromoacetonitrile (1.1 equiv.), using 2 equiv. DIPEA. Aqueous work up gave the title product, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][C:30](Cl)=[N:29][C:28]=23)=[O:23])[CH:7]=1.[NH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:36])[F:37])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][C:30]([NH2:38])=[N:29][C:28]=23)=[O:23])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3ccc(Cl)nc23)c1-c1cc(Cl)ccc1OC(F)F
Reactant: N
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3ccc(N)nc23)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 50 °C
Yield: 99 %

Procedure:
5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide (756 mg, 1.32 mmol) was dissolved in THF (10 mL) and concentrated aqueous ammonia (10 mL) added. The mixture was heated at 50° C. for 3 hours then allowed to cool to ambient temperature. The solvent was evaporated and the residue azeotroped with methanol (×2) to afford 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide as a white solid (724 mg, 99%). LCMS (Method 4) [M+H]+=549.9, RT=4.11 min.