Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 0.226 g (0.58 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.40 g (2.80 mmol) of 4-aminophenylacetic acid, methyl ester base was heated in a 160° C. to 165° C. oil bath. The resulting solution was heated for 10 minutes and cooled to room temperature. The solution was treated with 1 mL of glacial acetic acid to dissolve. Water (10 mL) was added to precipitate a gum. The mixture was decanted, and the remaining gum was dissolved in 20 mL of chloroform. The chloroform solution was washed with 25 mL of water, dried (magnesium sulfate), filtered, and concentrated. Purification was effected by silica gel chromatography eluting with chloroform and then with 50% hexane/ethyl acetate to obtain the fraction containing pure product. The eluent was concentrated to dryness to obtain a solid; wt 0.141 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH:22][C:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=3)=[O:33])[CH:19]=[CH:18][C:17]=2[F:23])([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cc(N)ccc2F)COC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)COC1
Reaction time: 14 h

Procedure:
[(R)-5-(5-Amino-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (75 mg, 0.22 mmol), 5-chloro-pyridine-2-carboxylic acid (38.1 mg, 0.242 mmol), HOAt (38.9 mg, 0.286 mmol), EDC (63.2 mg, 0.33 mmol) and Et3N (77 μl, 0.549 mmol) were dissolved in CH2Cl2 and stirred for 14 h. The solution was evaporated and the crude product was purified by chromatography on silica gel (heptane/EtOAc 6/1) to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([CH:20]2[CH2:22][CH2:21]2)=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl.O>[CH:20]1([C:5]2[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])=[CH:19][C:2]([NH:1][C:50]([C:46]3[O:45][CH:49]=[CH:48][CH:47]=3)=[O:51])=[C:3]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH2:27][CH2:28]3)[CH:4]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccccc1N1CCN(c2cc(C3CC3)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 5-amino-2-cyclopropyl-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 5b (66.0 mg, 0.14 mmol, 100 mol %) and N,N-diisopropylethylamine (0.07 ml, 0.42 mmol, 300 mol %) in dichloromethane (4.0 ml) was added furan-2-carbonyl chloride (0.02 ml, 0.21 mmol, 150 mol %) and a catalytic amount of N,N-dimethylaminopyridine. The reaction was stirred for 16 h at room temperature and then diluted with water and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford furan-2-carboxylic acid [4-cyclopropyl-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 5d (39.3 mg; 0.07 mmol, 49.7%) as an off-white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[I:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:14][CH2:15][N:16]([C:24]([C:23]4[CH:27]=[CH:28][C:20]([I:19])=[CH:21][CH:22]=4)=[O:25])[CH2:17][CH2:18]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 90.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 65 and using 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (5.52 g) described in Preparation Example 62, 4-iodobenzoyl chloride (6.35 g), the title compound (9.76 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].C(N1C=CN=C1)(N1C=CN=C1)=O.Br.[CH3:20][C:21]1([CH3:44])[CH2:30][CH2:29][C:28]([CH3:32])([CH3:31])[C:27]2[CH:26]=[C:25]([C:33]3[N:34]=[C:35]([CH:38]4[CH2:43]CNC[CH2:39]4)[S:36][CH:37]=3)[CH:24]=[CH:23][C:22]1=2.[CH3:45][N:46]([CH:48]=[O:49])[CH3:47]>>[CH3:20][C:21]1([CH3:44])[CH2:30][CH2:29][C:28]([CH3:31])([CH3:32])[C:27]2[CH:26]=[C:25]([C:33]3[N:34]=[C:35]([CH:38]4[CH2:39][CH2:47][N:46]([C:48]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:49])[CH2:45][CH2:43]4)[S:36][CH:37]=3)[CH:24]=[CH:23][C:22]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: COCCCO
Reactant: CN(C)C=O
Agent: Br
Agent: O=C(n1ccnc1)n1ccnc1
Product: COCCCOC(=O)N1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
41 μl (0.42 mmol) of 3-methoxy-1-propanol are dissolved in 3 ml of DMF, 69 mg (0.42 mmol) of 1,1′-carbonyldiimidazole are added, and the mixture is stirred at room temperature for 2 h. 122 mg (0.28 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-piperidine hydrobromide are subsequently added, and the reaction mixture is stirred at room temperature for 3 days. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and washed with 1 N HCl, saturated sodium hydrogencarbonate solution and saturated sodium chloride solution. The crude mixture is purified by column chromatography on silica gel. Yield: 90 mg of “A46”, ESI: 471 (M+H), HPLC: 4.20 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:25])[F:24])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[Na+:27].C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)=[O:26])[C:8]=1[O:9][CH3:10].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)=[O:26])[C:8]=1[O:9][CH3:10].[OH2:2].[OH2:2].[OH2:2].[Na+:27].[Na+:27]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Product: O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 212.5 %

Procedure:
Pantoprazole sodium (75 gms) as prepared according to Example-1 or Example-2 was dissolved in 375 ml of acetone at about 50-55° C., charcoal (5 gms) was added and the reaction mass was stirred for 15 minutes and clarified hot. The resulting clear filtrate was concentrated to approx. volume of 150 ml, ethyl acetate (400 ml) was added and distillation was continued until precipitation was observed in the reaction mass. The reaction mass was cooled to room temperature and water (4.2 ml) was added, the suspension was stirred for 1 hr. and later chilled and stirred at 0-5° C. for 1 hr. The product was the isolated by filtration and was dried at 40-45° C. under vacuum to give pantoprazole sodium sesquihydrate (68 gms.) having a moisture content of 6.5%.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:27]=[O:28])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=3)[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=4)[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:27]([OH:28])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 100 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 51 μL, 0.153 mmol) was added to a stirred solution of 9-chloro-1-(3,5-dichloropyridin-2-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (53.7 mg, 0.141 mmol) in tetrahydrofuran (1.0 mL) at 0° C., and the mixture was stirred at 0° C. for 50 min. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the title compound as a colorless solid (57.8 mg, 0.141 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[NH+:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:16][S:17]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)[O-])c2ccccc12
Product: c1cc[nH+]cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
A suspension of 4-amino-1-naphthalene sulfonic acid (200 g, 0.897 mole) in 800 ml of pyridine was stirred mechanically while methanesulfonyl chloride (70 ml, 0.9 mole) was added slowly over about 10 min. The reaction warmed to about 60° as the solid dissolved and then slowly cooled to room temperature. The mixture was stirred overnight while a solid precipitated. After filtering and washing with 500 ml of ether, the solid was dried under a nitrogen stream to afford 211 g (62%) of 4-methanesulfonamido-1-naphthalene sulfonic acid pyridinium salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([C:9](SC#N)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S-2:16].[Na+].[Na+].I[CH:20]([CH3:22])[CH3:21]>C(O)C.O>[NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([C:9]([S:16][CH:20]([CH3:22])[CH3:21])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1c(SC#N)ccc(N)c1C
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(SC(C)C)ccc(N)c1C
Temperature: 5 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A suspension of methyl 3-amino-2-methyl-6-thiocyanatobenzoate (22.2 g) in ethanol was added to a solution of sodium sulphide (26.6 g) in water. The resultant mixture was stirred at room temperature for 1 hour and then cooled to 5° C. 2-Iodopropane (19.36 g) was added and the mixture was allowed to warm to room temperature and stirred for 2 hours. It was evaporated to dryness and the residue was suspended in aqueous sodium chloride solution and extracted with dichloromethane. The organic layer was dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 3-amino-2-methyl-6-(1-methylethylsulphenyl)benzoate (18 g) as a yellow oil NMR(CDCl3) 1.2(d,6H) 2.0(s,3H) 3.0(m,1H) 3.8(bs,2H) 3.9(s,1H) 6.5(d,1H) 7.0(d,1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH:27](O)([CH3:29])[CH3:28]>>[CH:27]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16](/[CH:15]=[C:14](/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)\[CH3:25])=[CH:17][CH:18]=1)([CH3:29])[CH3:28]
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(C)O
Product: C/C(=C\c1ccc(C(=O)OC(C)C)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and isopropanol there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid isopropyl ester of melting point 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14]C1)[CH2:6][CH2:5]2.C(N)(=[O:20])C=C>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3[CH2:14][CH2:15][C:16](=[O:20])[NH:12][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CCC(N1CCCC1)=C2
Reactant: C=CC(N)=O
Solvent: CCO
Product: O=C1CCC2=C(CCc3cc(Cl)ccc32)N1

Procedure:
701 g (3 mol) of 1-(6-chloro-3,4-dihydro-2-naphthyl)-pyrrolidine and 640 g (19 mol) of acrylamide in 7 ml of ethanol are boiled under reflux for 3 days with the addition of 70 g of Amberlite IR200. The separated solid is removed by filtration, extractively crystallized with dioxane and there is obtained 8-chloro-1,4,5,6-tetrahydrobenzo[f]-quinolin-3(2H)-one with melting point 228°-230° C.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C=O.C1(C)C=CC=CC=1>O1CCCC1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (10.0 g, 21.9 mmol) is dissolved in 50 mL of anhydrous tetrahydrofuran, add iPr2NEt (3.7 g, 28.5 mmol) anhydrous Lithium chloride (490 mg, 11.0 mmol) and molecular sieves (2.0 g), refluxed for 30 min under nitrogen atmosphere, then add paraformaldehyde (790 mg, 26.3 mmol), reflux for 2 h under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 100 mL of toluene, filter to remove the molecular sieves, the filtration is washed with 5% HCl(aq)(50 mL*2), saturated Na2CO3 and brine, dry over anhydrous Na2SO4 and concentrate under vacuum to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl), which is direct used in next step. Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.Cl.[CH2:36]([NH2:39])[CH:37]=[CH2:38].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:36]([NH:39][C:27]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[O:33])[CH:37]=[CH2:38]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C=CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.2 ml), and a solution of triphosgene (50 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, allylamine hydrochloride (31 mg) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 21 mg (yield 33%) of the title compound.
Reaction SMILES: [OH:1][C:2]([C:19]([F:22])([F:21])[F:20])([CH2:16][C:17]#[CH:18])[CH2:3][C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([CH3:6])[CH3:5].N1C=CN=C1.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.C(OCC)C>[CH3:6][C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([CH3:5])[CH2:3][C:2]([C:19]([F:20])([F:21])[F:22])([O:1][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:16][C:17]#[CH:18]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CC(C)(C)c1ccccc1C(=O)O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCC(CC(C)(C)c1ccccc1C(=O)O)(O[Si](C)(C)C)C(F)(F)F
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 2-(3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzoic acid (345 mg, 1.10 mmol) and imidazole (374 mg, 5.49 mmol) in 1 mL of DMF was added chlorotrimethylsilane (0.42 mL, 3.29 mmol). The reaction mixture was stirred for 2 hours then diluted with 75 mL of diethyl ether, washed with two 50 mL portions of 1M aqueous HCl, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-(1,1-dimethyl-3-trifluoromethyl-3-trimethylsilanyloxy-hex-5-ynyl)benzoic acid (424 mg, 100%). MS (ES+) m/z 387 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(#N)C>[NH2:19][C:15]1[CH:14]=[C:13]([CH:8]([C:9]([F:11])([F:10])[F:12])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: CC(C)(C)OC(=O)CC(c1cccc(N)c1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
13.6 g (47.0 mmol) of (+/−)-tert-butyl-3-(3-aminophenyl)-4,4,4-trifluorobutanoate were initially charged in 100 ml of acetonitrile, and 6.28 g (47.0 mmol) of N-chlorosuccinimide were added at RT. The reaction mixture was initially stirred at 60° C. for 12 h and then allowed to stand at RT for 3 days. After concentration under reduced pressure, the residue was separated by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1), and the desired target product was isolated. This gave 4.49 g of the title compound (29.5% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1.CN(C)C=O>[CH:33]1([NH:39][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
11.15 g (0.05 mol) of N-benzyloxycarbonyl-L-alanine were dissolved in 75 ml of dry tetrahydrofuran and the mixture was cooled to -10° C. 6.35 ml (0.05 mol) of N-ethylmorpholine were added followed by 6.5 ml of isobutyl chloroformate and the solution obtained was stirred at -10° C. for 20 minutes. A solution of 6.05 ml of cyclohexylamine in 75 ml of tetrahydrofuran was then added and the resulting solution was stirred at 0° C. After 30 minutes the mixture solidified and 30 ml of dimethylformamide were added. After stirring for a further 1 hour at 0° C., the solvent was removed by evaporation, water was added and the solid filtered off. The solid was washed with 150 ml of 1-N hydrochloric acid, 150 ml of water, 150 ml of 5% sodium bicarbonate solution and 150 ml of water and then dried in vacuo. Recrystallisation from ethyl acetate yielded 11.7 g (77%) of N-benzyloxycarbonyl-L-alanine cyclohexylamide of melting point 163°-164° C.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+].CO.O>CCOC(C)=O>[CH3:26][O:27][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: C[C@@H](NCc1ccc(OCc2ccc(F)nc2)nc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(COc2ccc(CN[C@H](C)c3ccccc3)cn2)cn1

Procedure:
(1R)—N-((6-((6-Fluoro-3-pyridinyl)methoxy)-3-pyridinyl)methyl)-1-phenylethanamine (0.500 g, 1.48 mmol) was added to a microwave tube with NaOMe (0.400 g, 7.40 mmol) and MeOH (1.0 mL). The vial was sealed and irradiated for 7 min at 130° C. After the allotted time, the reaction was worked up by adding water (1.0 mL) and EtOAc (1.0 mL). The layers were separated and the aqueous layer was washed with EtOAc (3×1.0 mL). The combined organic layers were then washed with 1M sodium phosphate buffer (pH 5.5) (2×3.0 mL), dried over MgSO4, filtered, and concentrated to leave an oil. This was then purified by silica gel chromatography (1:1 hexane-EtOAc) to afford (1R)—N-((6-((6-methoxy-3-pyridinyl)methoxy)-3-pyridinyl)methyl)-1-phenylethanamine 2. MS m/z: 350 (MH+).
Reaction SMILES: CO[C:3]1[C:4](=O)[C:5](=[O:9])[C:6]=1[O:7]C.[CH2:11]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:11]([N:15]1[CH2:20][CH2:19][N:18]([C:3]2[C:6](=[O:7])[C:5](=[O:9])[C:4]=2[N:18]2[CH2:19][CH2:20][N:15]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17]2)[CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN1CCNCC1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCO
Product: CCCCN1CCN(c2c(N3CCN(CCCC)CC3)c(=O)c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.9 grams of 3,4-dimethoxy-3-cyclobutene-1,2-dione dissolved in 10 ml. of absolute ethanol is added 1.8 grams of 1-butylpiperazine in 5 ml. of absolute ethanol. The reaction mixture is stirred overnight at room temperature under a nitrogen atmosphere. Then, the solvent is removed with a nitrogen stream, 5 ml. of anhydrous ethyl ether is added, and the resultant solid is filtered, washed with ethyl ether, and dried in air. The resulting product, 3,4-bis(4-butyl-1-piperazinyl)-3-cyclobutene-1,2-dione is obtained as white crystals melting at approximately 137.5°-139° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.ClC1N([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])C=CC=N1.[CH2:25]([Cl:27])Cl>>[Cl:27][C:25]1[C:10]([S:19]([NH:22][C:23]([NH:11][C:4]2[N:3]=[C:2]([CH3:1])[C:7]3[CH2:8][CH2:9][CH2:10][C:6]=3[N:5]=2)=[O:24])(=[O:20])=[O:21])=[CH:6][CH:7]=[CH:2][N:3]=1
Reactant: ClCCl
Reactant: O=C=NS(=O)(=O)N1C=CC=NC1Cl
Reactant: Cc1nc(N)nc2c1CCC2
Product: Cc1nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)nc2c1CCC2

Procedure:
To a dry, stirred solution of 7.5 g of 6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-amine in 200 ml of methylene chloride at ambient temperature and pressure is added 13 g of 2-chloropyrimidine-3-sulfonylisocyanate. The resulting mixture is stirred at reflux for 2 hours and then concentrated at reduced pressure. The residue is triturated with 1-chlorobutane and filtered to yield the desired solid product.