Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:34]O)[CH2:33][CH2:32][CH2:31]1.[K+].[Br-]>>[CH:30]1([CH2:34][O:24][C:23]([C:18]2([C:20]([OH:22])=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:33][CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCC1CCC1
Agent: [Br-]
Agent: [K+]
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)OCC1CCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclobutylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO) δ 1.01 (d,3H), 1.75(m,4H), 1.92(m,2H), 2.49 (m, 1H), 2.65 (m,1H), 2.85-3.20 (m,4H), 4.09 (d, 2H), 4.85 (bt, 1H), 6.58 (d, 1H), 6.76 (m,2H), 7.35(m,3H), 7.46(s,1H); IR (KBr): 1652 cm- (C=O), 1761 cm-1 (C=O); MS (CI) m/z 490 (MH+). Anal. Calcd. for C25H28ClNO7 : C, 61.29; H, 5.76; N, 2.86; Cl, 7.24. Found: C, 57.13; H, 5.15; N, 2.43; Cl, 6.83.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:18][C:19](=[O:24])C(Cl)(Cl)Cl)=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)([O-:3])=[O:2].[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH2:30])[CH3:26]>>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][N:30]1[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:17]=2)[NH:18][C:19]1=[O:24])[CH3:26]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: CCN(CC)CCN
Product: CCN(CC)CCN1C(=O)Nc2ccc([N+](=O)[O-])cc2C1c1ccccc1

Procedure:
In similar way as in Preparation Example 1, the title compound was synthesized from 5-nitro-2-trichloroacetylaminobenzophenone and 2-(diethylamino)ethylamine.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.C(N(CC)CC)C>ClCCl>[C:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCCCCCn1c2ccccc2c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 30 mmol of methacryloyl chloride in 10 ml of dichloromethane was added dropwise to a solution of 25 mmol of N-(6-hydroxyhexyl)-carbazole and 30 mmol of triethylamine in 100 ml of dry dichloromethane. Thereafter, the reaction mixture was stirred for 3 hours at room temperature and then worked up by washing it with 2 N sodium hydroxide solution and water. After the reaction mixture had been evaporated down, the 6-(N-carbazolyl)-hexyl methacrylate formed was isolated by column chromatography over silica gel (eluent: dichloromethane). The 6-(N-carbazolyl)-hexyl methacrylate thus obtained in 70% yield was in the form of a colorless oil and had the following characteristic data:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=4[Cl:30])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Yield: 76.7 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-dichlorophenylboronic acid (3.73 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (75%) of (±)-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Anal. calcd. for C22H18Cl2O4S: C, 58.8; H, 4.04. Found: C, 59.01; H, 4.09.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]1[CH:40]=[C:39]([F:41])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:12]([F:42])[CH:11]=1.O=C1CCC(=O)N1[O:50][C:51](=O)[CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH:66][C:67](=[O:77])[CH2:68][CH2:69][N:70]1[C:74](=[O:75])[CH:73]=[CH:72][C:71]1=[O:76].CCN(C(C)C)C(C)C>>[O:76]=[C:71]1[CH:72]=[CH:73][C:74](=[O:75])[N:70]1[CH2:69][CH2:68][C:67]([NH:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([F:42])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:39]([F:41])[CH:40]=1)=[O:50])=[O:77]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CN)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid TFA salt (120 mg, 0.2 mmol), 3-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (103 mg, 0.2 mmol), and DIPEA (129 mg, 174 uL, 1.0 mmol), and after HPLC purification, resulted in a white solid (75 mg, 43%). ES(+)-HRMS m/e calcd. for C42H50F2N6O13 (M+Na)+ 907.3296, obsd. 907.3296.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nn2c(-c3ccc(Cl)c(N(C)S(C)(=O)=O)c3)ccnc2c1C#N
Yield: 60.7 %

Procedure:
A mixture of 0.048 g (0.39 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.124 g (0.39 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-methanesulfonamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 89 mg of N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 60.5%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH2:11]([NH2:13])[CH3:12]>C1COCC1>[CH2:11]([NH:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[CH3:12]
Reactant: CCN
Reactant: N#Cc1cccc(CBr)c1
Solvent: C1CCOC1
Product: CCNCc1cccc(C#N)c1
Reaction time: 5 h
Yield: 73 %

Procedure:
3-(Bromomethyl)benzonitrile (20.0 g, 0.1 mol) was added portion wise into a 2M solution of ethylamine in THF (150 mL) at 0° C. After 5 hours, the reaction mixture was concentrated under vacuum. The residue was taken up with water and extracted with DCM. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford the title compound as yellow liquid (12 g, 73%). 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.67 (d, 2H), 7.50 (m, 1H), 3.71 (s, 2H), 2.46 (m, 2H), 0.99 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CO.[Zn]>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:4]=[CH:5][C:6]=1[NH:9][C:33](=[O:34])[O:35][CH2:36][CH3:37]
Reactant: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1F
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1ccc(NCc2ccc(F)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.2 %

Procedure:
To a stirred solution of compound 3 (0.800 g, 2.86 mmol, 1.00 equiv) in methanol (7.2 mL) was added zinc powder (0.930 g, 14.3 mmol, 5.00 equiv) followed by ammonium chloride solution (0.760 g, 14.3 mmol, 5.00 equiv) dropwise. After being stirred at RT for 5 h, DIPEA (0.460 g, 3.58 mmol, 1.25 equiv) and ethyl chloroformate (0.310 g, 2.87 mmol, 1.00 equiv) were added to reaction mixture at 10° C. and the stirring was continued for another 3 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (24 mL) and stirred for 1 h to give the solid. The obtained solid was filtered, dissolved in EtOAc (15 mL) and again filtered the un-dissolved solid. The filtrate was evaporated and recrystallized using n-hexane to afford compound 1A (0.250 g, 27.0%) as brown solid. TLC: 50% EtOAc/Hexane (Rf: 0.20) 1H NMR (500 MHz, CDCl3): δ 7.31 (t, J=7.5 Hz, 2H), 7.02 (t, J=6.8 Hz, 2H), 6.75 (d, J=6.8 Hz, 1H), 6.07 (t, J=6.8 Hz, 1H), 4.31 (s, 2H), 4.22-4.18 (m, 3H), 3.84 (br s, 2H, Exc), 1.29 (t, J=5.6 Hz, 3H); UPLC purity: 91.0%; LC-MS: m/z=322 (M+-1) at RT 3.37 (82.8%)
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[O:27])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26]([C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=[CH:30][CH:29]=4)=[O:27])[CH2:21][CH2:20]3)[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=CC[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1)c1ccnc2ccccc12
Reaction time: 8 h

Procedure:
4-(4-fluorobenzoyl)piperidine (trifluoro-acetic acid salt) (0.020 g, 0.062 mmol) was solved in 1,2-dichloromethane (0.300 mL) and Quinoline-4-carboxylic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-amide (0.020 g, 0.067 mmol) was added. Methanol (0.200 mL) was added to the mixture and it was stirred overnight. Sodium triacetoxyborohydride (0.024, 0.11 mmol) was added to the clear solution that was stirred 10 hours at room temperature. The mixture was concentrated to dryness and the residue was taken up on methanol and purified with preparative HPLC on reversed phase eluting with acetonitrile/water. The combined producted fractions were evaporated under reduced pressure to yield 0.03 g of a white solid (0.06 mmol, 99%). MS (m/e): 488.3 (M+H+)
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:24][CH:23]=1)=O>>[CH3:30][N:28]([CH3:29])[C:26](=[O:27])[C:25]1[CH:31]=[CH:32][C:22]([CH2:20][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:24]=1
Reactant: CN(C)C(=O)c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CN(C)C(=O)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-formyl-N,N-dimethylbenzamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41]>C(OCC)(=O)C>[Cl:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([CH3:23])=[CH:5][N:4]=[CH:3][C:2]=1[CH3:1]
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1O
Reactant: ClCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-(3,5-dimethylpyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (1.46 g, 4.7 mmol), cesium carbonate (1.83 g, 5.6 mmol), and DMSO (15 mL) was stirred at room temperature for 15min, and then 1-bromo-6-chlorohexane (0.83 mL, 5.6 mmol) was added. After 45 min, the reaction was diluted with ethyl acetate, washed with water (×3), dried, filtered, concentrated, and then triturated with hexane/diethyl ether to remove the excess 1-bromo-6-chlorohexane. The solid residue was purified by silica gel chromatography (49:1→23:2; dichloromethane/methanol) to give 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one. 1H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.38 (s, 2H), 7.42 (d, 1H), 6.90 (d, 1H), 6.05 (s, 1H), 5.13 (d, 1H), 4.12 (t, 2H), 3.97 (s, 3H), 3.56 (t, 2H), 2.21 (s, 6H), 1.82 (m, 4H), 1.52 (m, 4H); MS (ESI): 430.3.
Reaction SMILES: C1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([Cl:9])[Cl:8])C=CC=CC=1.[Cl:16][SiH](Cl)Cl>[Cl-].[Al+3].[Cl-].[Cl-]>[C:10]1([Si:7]([Cl:8])([Cl:9])[Cl:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cl[SiH](Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)c1ccccc1
Yield: 116.5 %

Procedure:
380 g of diphenyldichlorosilane, 22.5 g of anhydrous aluminium chloride and 2.3 g of anhydrous alumina (specific surface area : 0.1 m2 /g) are placed in a flask. 477 g of trichlorosilane are run in over the course of 6 hours 50 minutes, whilst keeping the reaction mixture at 70°C and distilling the dichlorosilane. A fraction weighing 76 g, containing 74% of dichlorosilane, is obtained. 370 g of phenyltrichlorosilane are obtained on distilling the mixture remaining in the flask.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12](=[O:20])[CH2:13][CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][C:12]([NH:11][CH3:10])=[O:20])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)CCNCC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)CCN(CC(C)C)c1nc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
5-Bromo-2,4-dichloropyrimidine (Aldrich; 2.82 g, 12.37 mmol), N-methyl-3-(2-methylpropylamino)propanamide (Intermediate 86; 1.78 g; 11.25 mmol), Triethylamine (1.65 mL, 11.81 mmol) and DCM (40 mL) were combined and stirred over the weekend at room temperature. The reaction mixture was washed saturated aqueous sodium bicarbonate solution and gravity filtered through a PTFE cup and solvent evaporated. The residue was dissolved in DCM and passed through a silica column eluting with a gradient of 30-50% Ethyl Acetate/iso-hexane over 10 column volumes then 50% Ethyl Acetate/iso-hexane. Fractions containing product combined and evaporated to give the title compound as a white solid. (3.26 g, 83%)
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].[Cl-].[Na+]>CN(C)C=O>[Cl:11][C:4]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:2]([NH:24][CH2:23][C:22]([F:26])([F:25])[F:21])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Reactant: NCC(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2NCC(F)(F)F)c(F)c1
Yield: 84.1 %

Procedure:
A solution of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine (16 mg, 0.05 mmol) and 2,2,2-trifluoroethylamine (200 mg, 2.0 mmol) in 1 mL of N,N-dimethylformamide is stirred at room temperature for 16 h. A saturated sodium chloride solution is added, and the product is extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of 20% ethyl acetate in hexanes to 50% ethyl acetate in hexanes. Concentration provides 7-chloro-N-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidin-5-amine as a white solid (16 mg, mp 155-157° C.). MS: m/z 381.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH:5]([CH3:8])[CH2:6][OH:7].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:14][S:15]([O:7][CH2:6][CH:5]([O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])[CH3:8])(=[O:17])=[O:16]
Reactant: CC(CO)Oc1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)Oc1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 324 parts of 2-(2,4-dichlorophenoxy)-1-propanol and 700 parts of N,N-diethylethanamine were added dropwise at room temperature 335 parts of methanesulfonyl chloride (exothermic reaction: the temperature roses to reflux temperature). While cooling in a water-bath, stirring was continued for 30 minutes at room temperature. The reaction mixture was poured onto water and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated. The residue was distilled by vacuum distillation, yielding 300 parts of 2-(2,4-dichlorophenoxy)-1-propanol methanesulfonate (ester); bp. 130° C. at 2×10-4 mm. pressure (intermediate 101).
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:40])=[O:5])[S:12][CH:13]=3)=[C:20]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])[CH:21]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2C(=O)N2CCOCC2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2C(=O)N2CCOCC2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
2-{[4-(2-{[4′-Fluoro-3-(morpholin-4-ylcarbonyl)biphenyl-4-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (180 mg) obtained in Example 93-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (120 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (1.5 g, 4.27 mmol) and ethyl 2-aminoacetate (696 mg, 5.12 mmol). The title compound was obtained as a solid (1.1 g, 59% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.36 (1H, t), 8.98 (2H, s), 8.47 (1H, s), 4.11 (2H, q), 3.97 (2H, s), 1.19 (3H, t). MS m/z: 434.08, 436.06 [M+H]+.
Reaction SMILES: O1CCCCC1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:15][C:10]=2[N:9]=[CH:8]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[CH:29]=2)[CH:24]=[CH:23][N:22]=1>>[NH:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([NH:19][C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[C:30]([CH:33]5[CH2:35][CH2:34]5)[NH:31][N:32]=4)[CH:24]=[CH:23][N:22]=3)([CH3:17])[CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CC(C)(N)c1ccc2c(c1)ncn2C1CCCCO1
Product: CC(C)(Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1ccc2[nH]cnc2c1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
A neat mixture of 94 (691 mg, 2.67 mmol) and 53 (210 mg, 0.89 mmol) was stirred under nitrogen at 140° C. for 18 h. The dark brown mixture was cooled to RT and was purified by preparative HPLC to afford 25 mg (7.5%) of I-17 as white solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:3]=1.C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[CH:8]([Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:4]1[CH:5]=[CH:6][C:2]([CH:25]=[O:26])=[CH:3]1)([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C=O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To a solution of 3-bromo-1-(triisopropylsilyl)-1H-pyrrole (2.0 g, 6.61 mmol) in THF (30 mL) was added n-butyllithium (2.5 M in hexanes, 3.4 mL, 8.60 mmol) at −78° C. The mixture was stirred at −78° C. for 10 min then DMF (0.76 mL, 9.92 mmol) was added and the mixture was warmed to 0° C. over 1 hour. The reaction mixture was quenched by saturated NH4Cl and extracted with EtOAc (200 mL). The organic phase was washed with brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% EtOAc in hexanes) to afford the sub-title compound (1.65 g, 100%).