Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(Nc2ccccc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with aniline following the procedure described for 4-[(butyl)-(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[O:19][CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN1CCCC1=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[O:19][CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: O=c1[nH]cccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 90 °C
Reaction time: 6 h

Procedure:
36.2 g of 3-bromopyridone (87% purity, 0.18 mol) and 29.4 g of 4-fluoro-3-methoxynitrobenzene (0.17 mol) were introduced as initial charge in 180 ml of N-methylpyrrolidone; 46.1 g of anhydrous potassium phosphate (0.22 mol) were added and the reaction mixture was carried out at 120° C. for 6 h. After cooling to 90° C., water was added and the mixture was cooled to room temperature. The precipitate was filtered off, washed with water and stirred with a methanol/water mixture (1:1). The solid was filtered off, washed and dried in the air. This gave 38.7 g (66%) of the desired target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: Cc1cncc(Br)c1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cncc(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 3-bromo-5-methylpyridine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]1>>[OH:41][CH2:40][CH:37]1[CH2:38][CH2:39][N:34]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:35][CH2:36]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: OCC1CCNCC1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCC(CO)CC1
Yield: 40 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalents of 4-piperidinylmethanol as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]1[C:21]2[CH:20]=[C:19]([Cl:22])[N:18]=[CH:17][C:16]=2[CH:15]=[C:14]1[CH:23]([CH3:25])[CH3:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:29]=[O:30])C>>[CH2:6]([N:13]1[C:21]2[CH:20]=[C:19]([Cl:22])[N:18]=[CH:17][C:16]=2[C:15]([CH:29]=[O:30])=[C:14]1[CH:23]([CH3:25])[CH3:24])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(C)c1cc2cnc(Cl)cc2n1Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1c(C=O)c2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
POCl3 (0.31 ml, 3.42 mmol) was added to anhydrous DMF (5 ml) at 0° C. slowly and stirred for 20 min. To this solution was added a solution of 1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine (Compound 13, 195 mg, 0.68 mmol) in anhydrous DMF (7 ml) at room temperature. The mixture was stirred at room temperature for 2 h and was then heated to 60° C. for 2 h and 80° C. for 0.5 h. The reaction was cooled to room temperature, quenched cautiously with aqueous Na2CO3, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:35]([NH2:37])[CH3:36]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[NH:37][CH2:35][CH3:36]
Reactant: Cc1ccc2ccccc2c1O
Reactant: CCN
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: CCNc1c(C)ccc2ccccc12
Yield: 85 %

Procedure:
316 parts of 2-methyl-α-naphthol, 10 parts of triphenyl phosphite and 115 parts of ethylamine gas are heated for 20 hours at 230° C in a pressure autoclave. The further working up is carried out as described in Example 3. 315 parts of 2-methyl-N-ethyl-α-naphthylamine, boiling at 120° - 125° C/0.3 mm Hg (nD25 = 1.6145) are obtained, corresponding to a yield of 85% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1
Reactant: N
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2CCc2ccccc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 372) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.075 g, 17%). semi-solid; 1H NMR (300 MHz, DMSO d6) δ 2.80 (m, 4H), 3.29-3.42 (3H, obstructed by H2O), 6.96 (m, 2H), 7.14-7.28 (m, 3H), 7.46-7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 466 (M+H)+, 483 (M+NH4)+. Anal. calc. for C24H20ClN2O3S.0.25H2O: C, 61.27; H, 4.39; N, 8.93. Found: 61.18; H, 4.68; N, 8.58.
Reaction SMILES: [C:1]12[CH2:8][CH2:7][C:6]=1[CH:5]=[CH:4][CH:3]=[CH:2]2.[Br:9]Br.S([O-])([O-])=O.[Na+].[Na+]>O.CCCCCC>[Br:9][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][C:1]=2[CH:2]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)CC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Brc1ccc2c(c1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bicyclo[4.2.0]octa-1(6),2,4-triene 5a (7.9 g, 76 mmol) was dissolved in 80 mL of water at room temperature. Upon cooling by an ice-water, 3.9 mL of bromine was added dropwise. Upon completion of the addition, the ice-water bath was removed and the reaction mixture was warmed up to room temperature and stirred overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of n-hexane and sodium sulfite (3 g, 23.8 mmol) was added. Upon completion of the addition, the mixture was stirred at room temperature for 30 minutes. Then the separated organic layer was dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 3-bromo-bicyclo[4.2.0]octa-1(6),2,4-triene 5b (13.53 g) as a colourless oil, which was directly used in the next step.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)[C:49]=1[C:50](O)=[O:51]>>[F:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)[C:49]=1[C:50]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:51]
Reactant: O=C(O)c1c(F)cccc1-n1cccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1c(F)cccc1-n1cccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 2-fluoro-6-(1H-pyrazol-1-yl)benzoic acid (CAS number 1521055-55-9; 75 mg, 0.37 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:29]3[C@H:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
N,N'-Carbonyldiimidazole (2.43 g) is added to a solution of 2-dimethylaminophenylacetic acid (2.68 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred at +5° C. for 90 minutes and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (4.9 g) and triethylamine (4.2 cc) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 5 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 125 cc fractions. Fractions 5 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (40 cc) and isopropyl ether (200 cc). The crystals are drained, washed with isopropyl ether and dried. (3aR,7aR)-7,7-diphenyl-2-[2-(2-dimethylaminophenyl)acetyl]-4-perhydroisoindolone (2.58 g) is obtained in the form of white crystals, melting at 190° C.; [α]D20 =-242° (c=1.18, chloroform)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][OH:20])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2CCC1(CO)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.99 g of the title compound of Step C and 0.6 ml of methanesulfonyl chloride in 20 ml of THF at 0° C. was added 1.05 ml of triethylamine. The reaction was stirred overnight at room temperature, partitioned between 5% aqueous sodium bicarbonate and chloroform, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane to afford 1.1 g of the title compound as a viscous yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:8][CH:7]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:10][CH:11]=1
Reactant: COCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCOc1ccc(CCC2(O)CN3CCC2CC3)cc1
Yield: 38.4 %

Procedure:
A mixture of 3-[2-{4-(2-methoxyethoxy)phenyl}ethynyl]-quinuclidin-3-ol (1.8 g) in ethanol (200 ml) and a catalyst of 10% (v/v) palladium on carbon (100 mg) was stirred under an atmosphere of hydrogen until hydrogen uptake ceased. The palladium/carbon catalyst was removed by filtration and the filtrate was evaporated. The residue was crystallised from a 3:1 (v/v) mixture of cyclohexane ethylacetate to give 3-[2-{4-(2-methoxyethoxy)phenyl}ethyl]quinuclidin-3-ol (700 mg) as a solid, mpt 116-117° C. Microanalysis, found C,71.1; H,9.2; N,4.5%; C18H27NO3 requires: C,70.8; H,8.9; N,4.59%; NMR ([CD3 ]2SO): 1.15-1.35 (1H, m), 1.4-1.6 (1H, m), 1.65-1.78 (2H, m), 1.9-2.08 (1H, m), 2.45-2.8 (10H, m), 3.3 (3H, s), 3.6-3.68 (2H, m), 4.0-4.08 (2H, m), 4.3 (1H, br), 6.78-6.86 (2H, d), 7.05-7.13 (2H, d); m/z 306 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=1)=[O:6].[CH2:25]([C:29]1[CH:34]=[CH:33][C:32]([CH:35](Cl)[C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:38][CH:37]=2)=[CH:31][CH:30]=1)[CH:26]([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:42]([C:39]1[CH:40]=[CH:41][C:36]([CH:35]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=2)=[O:6])[C:32]2[CH:33]=[CH:34][C:29]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:30][CH:31]=2)=[CH:37][CH:38]=1)[CH:43]([CH3:45])[CH3:44]
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Reactant: Nc1cccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 4-[3-(3-aminobenzoyl)indol-1-yl]butyric acid (880 mg), bis(4-isobutylphenyl)methyl chloride (1.03 g) and diisopropylethylamine (0.945 g) in dichloromethane (20 ml) was stirred at 25° C. overnight, and bis(4-isobutylphenyl)methyl chloride (170 mg) and diisopropylethylamine (86 mg) were added thereto. After stirring at 25° C. for 3 hours, the reaction mixture was poured into cold 1N hydrochloric acid. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (100 g) with a mixture of chloroform and methanol (50:1) as eluent and freeze-dried from benzene to give 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]butyric acid (820 mg) as pale yellow powder.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 74.5 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 1.22 ml (4.96 mmol) of myristoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.17 g of the desired compound (74.5%, colorless powder), mp: 80.0°-81.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][NH2:43]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:43][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([NH2:38])[CH:40]=2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCc1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2cccc(N)c2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 3-aminobenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 1.27-1.39 (m, 3H) 4.18-4.75 (m, 4H) 6.31-7.50 (m, 5H). MS (ESI) positive ion 312 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:4]=[N:3][CH:2]=1.[N+:12]([CH:15]=[C:16](SC)SC)([O-:14])=[O:13].CS>C(O)C>[N:1]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:16]2=[CH:15][N+:12]([O-:14])=[O:13])[CH:4]=[N:3][CH:2]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCNCc1cncnc1
Agent: CS
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCN1Cc1cncnc1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of N-(5-pyrimidinylmethyl)ethylenediamine (15.2 g), 1-nitro-2,2-bis(methylthio)ethylene (14.9 g) and ethanol (100 g) was refluxed with stirring until the generation of methylmercaptan ceased (for about 3 hours). The reaction mixture was cooled to room temperature, and the resultant crystals were collected by filtration. The crystals were washed with ethanol, and dried to give 1-(5-pyrimidinylmethyl)-2-(nitromethylene)imidazolidine (12.7 g) as pale yellow crystals. This product decomposes at 236° C.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](O)=[O:27])(=[O:19])=[O:18])=[O:15])[N:6]=1.Cl>CCOCC.O1CCCC1>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[O:27])[CH3:1])(=[O:19])=[O:18])=[O:15])[N:8]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Reaction time: 4 h

Procedure:
A methyllithium solution in ether (1.4M, 40 ml) was added to a solution of 1.0 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-carboxybenzenesulfonamide in 50 ml of dry tetrahydrofuran at room temperature. The resulting yellow slurry was stirred for 4 hours and the dilute hydrochloric acid was added. The mixture was then extracted with methylene chloride. The organic extracts were washed, dried, and evaporated in vacuo to dryness. The crude product was purified by preparative TLC, eluted with ethyl acetate/hexane (1:1), m.p. 126°-128° C.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][Cl:27])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCCl
Temperature: 45 °C
Yield: 33.8 %

Procedure:
A mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.2 g, 3.3 mmol), (prepared as described for the starting material in Example 48), 1-bromo-3-chloropropane (1.6 ml, 16 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (25 ml) was heated at 45° C. for 3 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×70 ml). The organic extracts were combined, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with hexantlethyl acetate, collected by filtration and dried under vacuum to give 4-(4-bromo-2-fluoroanihno)-7-(3-chloropropoxy)-6-methoxyquinazoline (492 mg, 34%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][C:34]([CH3:37])([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: CC(C)(O)CN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(C)(C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.3 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (300 mg, 0.673 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and 1-amino-2-methyl-2-propanol (150 mg, 1.68 mmol), WSCI.HCl (185 mg, 0.965 mmol) and 4-dimethylaminopyridine (165 mg, 1.35 mmol) were added, followed by stirring at room temperature for 17 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (307 mg, yield 88%) as a white solid.