Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:14][NH:13][CH2:12]2)[CH3:10])=[N:6][CH:7]=1.CCN(CC)CC.[Br:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl>[Br:31][CH2:32][C:33]([N:13]1[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH:11]([CH:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH3:10])[CH2:12]1)=[O:34]
Reactant: O=C(Cl)CBr
Reactant: CC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Cl)cn1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 95.2 %

Procedure:
To a stirred solution of 5-chloro-2-{(RS)-1-[(3SR,4RS)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-pyridine (XV-B-2) 0.12 g (0.32 mmol) in CH2Cl2 (10 mL) at RT, 0.055 ml (0.38 mmol) of Et3N and 0.032 mL (0.33 mmol) of bromo-acetyl chloride were added. Stirring was continued over night and then concentrated under vacuo. The crude residue was dissolved in EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product was purified by flash chromatography (SiO2, EtOAc) to yield the title product 0.15 g (92%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][C:11]#[CH:12])=[O:7])([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:37][C@H:38]([C:43]([O:45][CH3:46])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41].Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:2]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]#[CH:12])[C:13]([NH:37][CH:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:43]([O:45][CH3:46])=[O:44])=[O:15])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCC(NC(=O)OC(C)(C)C)C(=O)NC(CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of Boc-L-propargylglycine (26.65 g; 125 mmol) in dry DMF (170 mL) was added EDCI (29.23 g; 152.5 mmol) and HOBt (23.5 g; 122.5 mmol), and the reaction mixture was stirred at room temperature for 40 min (solution A). In a separate RB flask, (L) Leu-OMe hydrochloride (22.72 g; 125 mmol) in dry DMF (82 mL) kept at 0° C. was treated with diisopropyl ethyl amine (DIEA) (64.62 g; 500 mmol) and the solution was stirred for 25 min (solution B). Solution B was added to solution A and the reaction mixture was stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in dichloromethane (DCM) (600 mL) and washed sequentially with saturated sodium bicarbonate (2×200 mL), 5% HCl (2×200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, leaving a crude product which was purified using flash chromatography (silica gel; hexane/ethyl acetate 75:25) to give 1 as a white solid (38.12 g; 89% yield); 1H NMR (CDCl3) δ 8.2 (s, 1H), 7.0 (s, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.6 (s, 3H), 2.8 (s, 1H), 2.4 (m, 2H), 2.3 (m, 1H), 1.6 (m, 2H), 1.5 (m, 1H), 1.38 (s, 9H), 0.87 (d, 6H).
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[C:11](Br)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[O-2].[Mg+2].[H][H].Cl>O.CO.[Pd].O>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][N:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1nc(Br)c2n1CCC2C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [Mg+2]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1ncc2n1CCC2C(=O)O

Procedure:
Three (3) grams of 3-benzoyl-1-bromo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-7-carboxylic acid were dissolved in 200 ml of a 50% water/methanol mixed liquid, containing 0.7 g of sodium hydroxide incorporated with 1.5 g of magnesium oxide and 0.6 g of 5% palladium/carbon and then agitated to the extent that absorption of the hydrogen gas is stopped (about 4 hours). After the end of the reaction, the reaction mixture was filtered and washed several times with water and methanol. The filtrate was concentrated under a reduced pressure and washed twice with about 70 ml of ethyl acetate. The aqueous layer obtained was made weakly acidic with conc. hydrochloric acid to precipitate crystals which were then filtered off. The rough crystals obtained were water washed, air-dried and then recrystallized from ethanol to obtain 2.1 g of 3-benzoyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-7-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(F)c1

Procedure:
The title compound, MS: m/e=312.5 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-fluorobenzene boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:27][N:26]=[N:25][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1.IC.[C:39](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[N:27]([CH3:39])[N:26]=[N:25][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2nnnn2C)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 48 h
Yield: 36.1 %

Procedure:
To 2.7 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1H-tetrazol-5-yl)methyl]benzenesulfonamide dissolved in 50 ml of DMF are added, at room temperature, 1.07 g of iodomethane and 1.04 g of potassium carbonate. After 48 hours at room temperature, the medium is poured into water and then extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) toluene/ethyl acetate mixture to give 1 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(1-methyl-1H-tetrazol-5-yl)methyl]benzenesulfonamide (compound 152) 1H NMR δ in ppm (DMSO d6): 3.81 (s, 3H); 3.90 (s, 3H); 3.93 (q, 1H); 4.05 (m, 4H); 4.93 (d, 1H); 5.42 (d, 1H); 6.58 (s, 1H); 7.00 (d, 1H); 7.10-7.46 (unresolved complex, 7H). m.p.=180.8° C. and 0.71 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-3,4-dimethoxy-N-[(2-methyl-2H-tetrazol-5-yl)methyl]benzenesulfonamide (compound 151) 1H NMR δ in ppm (DMSO d6): 3.81 (s, 3H); 3.89 (s, 3H); 4.13 (s, 2H); 4.26 (s, 3H); 4.77 (d, 1H); 5.25 (d, 1H); 6.57 (s, 1H); 6.86 (d, 1H); 7.11-7.47 (unresolved complex, 7H). m.p.=136.3° C.
Reaction SMILES: N#N.C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]=[CH2:14])[CH2:9][CH2:8]1)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:13]([CH:10]1[CH2:11][CH2:12][CH:7]([CH2:5][OH:4])[CH2:8][CH2:9]1)=[CH2:14]
Reactant: C=CC1CCC(C(=O)OC)CC1
Agent: COCCO[Al+]OCCOC
Agent: N#N
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=CC1CCC(CO)CC1
Reaction time: 2 h
Yield: 109.3 %

Procedure:
A 1 liter three-necked flask, equipped with thermometer, stirrer and N2 protection, was used. 46.2 g of 4-vinylcyclohexyl formic acid methyl ester and 140 ml of toluene were added to obtain a pale yellow solution. The temperature was decreased with an ice-water bath. A solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene in an amount of 1.2 times higher than the theory amount was added dropwise, and the temperature was controlled to be less than 30° C. After the completion of addition, the temperature was controlled to be at 30° C., and kept at that temperature for 2 hours. The mixture was poured into 220 g of an aqueous solution of 20% NaOH, the temperature was controlled to be less than 30° C., and stirred for half an hour. The organic phase was separated out, the aqueous phase was extracted twice with 300 ml of THF, the organic phases were combined, and the solvent was removed by a rotary evaporator, to obtain 42.1 g of pale yellow liquid. GC purity: 94.4%, wherein cis 38.0%, and trans 56.4%.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@:24]([CH3:30])([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Li+]>O1CCCC1>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@:24]([CH2:26][OH:27])([CH3:30])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC(=O)[C@@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
To a solution of methyl(2R,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-methyl-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 44, 69 mg, 0.112 mmol) in Tetrahydrofuran (THF) (2.5 ml) at 0° C. lithium borohydride (0.164 ml, 0.335 mmol) was added and the reaction mixture was stirred at room temperature and under nitrogen atmosphere for 3 days. Volatiles were evaporated in vacuo and the residue was dissolved in Methanol (2 ml)/HCl 1 N in water (3 ml). After 1 h stirring combined solvents were evaporated in vacuo. The residue was dissolved in Ethyl acetate (4 ml) and washed with NaHCO3 sat. sol. (2×3 ml). Organic phase was dried and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage SNAP 10 g as column and Dichloromethane/Methanol 95:5 as eluent affording the title compound (28 mg, 0.047 mmol, y=66.8%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[C:5]1[C:15](=[O:16])[CH:14](C(OCC)=O)[CH2:13][CH2:12][N:6]12.Cl.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[C:5]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][N:6]12
Reactant: CCOC(=O)C1CCn2c(c(Sc3ccc(Cl)cc3)c3c(Br)cc(F)cc32)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1CCCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Yield: 64.3 %

Procedure:
To a solution of the ketoester of Step 3 (400 mg) in EtOH (10 mL) at r.t. was added 3 mL of concentrated HCl. The reaction mixture was stirred at reflux for 4 hours, cooled and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The residue was swished in EtOAc to provide 220 mg of the title compound as a yellow solid.
Reaction SMILES: NC1C(F)=C([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])N=C(C(OC(C)C)=O)C=1.[C:25]([NH:28][C:29]1[C:34]([F:35])=[C:33](Br)[N:32]=[C:31]([C:37]([O:39][CH3:40])=[O:38])[CH:30]=1)(=[O:27])[CH3:26]>>[C:25]([NH:28][C:29]1[C:34]([F:35])=[C:33]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:32]=[C:31]([C:37]([O:39][CH3:40])=[O:38])[CH:30]=1)(=[O:27])[CH3:26]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Reactant: COC(=O)c1cc(NC(C)=O)c(F)c(Br)n1
Product: COC(=O)c1cc(NC(C)=O)c(F)c(-c2ccc(Cl)c(OC)c2F)n1

Procedure:
Methyl 4-(acetylamino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate was prepared in analogous fashion to isopropyl 4-(amino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate in Example 10 except that methyl 4-acetamido-6-bromo-5-fluoropicolinate was used in place of isopropyl 4-amino-6-bromo-5-fluoropicolinate: mp=189-191° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H), 9.04 (d, JF-H=5.6 Hz, 1H), 7.53 (dd, J=8.4, 1.6 Hz, 1H), 7.37 (dd, J=8.4, 7.0 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.22 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 170.3, 164.1, 154.4, 151.9, 149.4, 146.7, 144.1-143.8 (m), 140.5 (d, JF-C=15.3 Hz), 135.1 (d, JF-C=10.8 Hz), 128.9 (d, JF-C=3.4 Hz), 125.9 (dd, JF-C=35.0, 3.5 Hz), 122.9 (dd, JF-C=13.7, 3.5 Hz), 61.6, 52.6, 24.1; 19F {1H} NMR (376.5 MHz, DMSO-d6) δ −129.5 (d, JF-F=27.5 Hz), −142.8 (d, JF-F=27.5 Hz); IR: 3341, 2972, 2944, 1733, 1705, 1599, 1507, 1439, 1416, 1406, 1371, 1283, 1166, 1039, 974, 926, 890, 823, 678; MS Calcd. for C16H13ClF2N2O4: 370.1. Found: 370 (M+), 312.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:17]4[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC12CCCc3cc(N)cc(c31)CCC2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2cc3c4c(c2)CCCC4(C)CCC3)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
6a-Methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.290 g) and ethyl 4-iodobenzoate (0.390 g) were dissolved in anhydrous toluene (5 ml), the solution was added with tris(dibenzylideneacetone)dipalladium (0.026 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.036 g), and cesium carbonate (0.493 g), and the mixture was stirred overnight at 80° C. under an argon flow. The reaction mixture was left to cool and then poured into ice water, and the mixture was extracted with diethyl ether. The organic layer was washed successively with 2 N aqueous hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:50) to obtain the title compound (0.261 g, yield: 52%). The compound was recrystallized from chloroform-n-hexane to obtain colorless needles (melting point: 135-137° C.).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:19](OC)(OC)(OC)C>CO>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: COC(C)(OC)OC
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
25.50 g (0,127 mol) of 2-chloro-3-nitrobenzoic acid are dissolved in 50 ml of MeOH, and 3 ml of concentrated sulfuric acid are added. The reaction mixture is heated at boiling for 4 h. Following the addition of 10 ml of trimethyl orthoacetate the mixture is heated at boiling for a further 2 h. After cooling to 0° C. and filtering off the solid by suction, 26.4 g (96 %) of colorless methyl 2-chloro-3-nitrobenzoate are obtained, m.p. 68-70° C.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:8]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:32]([O:31][C:30]([N:20]1[CH2:21][CH2:22][N:17]([C:9]2[N:8]=[C:7]([O:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][OH:1])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:18][CH2:19]1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OC/C=C\COc1nc(N2CCNCC2)nc2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2nc(OC/C=C\CO)c3ccccc3n2)CC1

Procedure:
To a solution of 4-[cis-(4-hydroxybut-2-en-1-yl)oxy]-2-(1-piperazinyl)quinazoline (1.09 g) in dry methylene chloride (25 ml) is added triethylamine (1.52 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (0.62 ml) in dry methylene chloride (5 ml). The mixture is stirred under ice-cooling for 1.5 hour. The reaction mixture is diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=50:1, v/v) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[cis-(4-hydroxybut-2-en-1-yl)oxy]quinazoline (1.52 g) as oil.
Reaction SMILES: Cl[C:2]([C:4]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([CH3:22])[CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]([C:4]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:3])=[C:17]([CH3:22])[CH:16]=1
Reactant: CCOC(=O)C1(C(=O)Cl)CCCC1
Reactant: Cc1cc(Br)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CCCC1
Yield: 35 %

Procedure:
Ethyl 1-chlorocarbonylcyclopentanecarboxylate (3.10 grams, 0.02 mole) prepared in Example XX, 4-bromo-2-methylaniline (2.82 grams, 0.02 mole) and triethylamine (1.53 grams, 0.02 mole) were reacted in tetrahydrofuran (200 milliliters) under conditions similar to those described in Example I to give 2.40 grams (0.007 mole) of ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopentanecarboxylate which, after recrystallization from hexane, had a melting point of 64° C.-67° C.
Reaction SMILES: [C:1]([CH:4]([C:9](=O)[CH3:10])[CH2:5][CH2:6][C:7]#[N:8])(=[O:3])[CH3:2].[H][H]>C(O)C.[Ni]>[C:1]([C:4]1[CH2:5][CH2:6][CH2:7][NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C(CCC#N)C(C)=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)C1=C(C)NCCC1

Procedure:
A solution of 4,4-diacetylbutyronitrile (15.3 g, 0.1 mole) in ethyl alcohol (50 ml) over Raney nickel (2 g) was hydrogenated at room temperature and three atmospheres pressure. After hydrogen uptake had ceased, the catalyst was filtered off and the filtrate concentrated under reduced pressure to give 3-acetyl-2-methyl-1,4,5,6-tetrahydropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][C@H:21]([NH:23][CH3:24])[CH3:22])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:25].[C:26]([OH:29])(=O)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][C@H:21]([N:23]([CH3:24])[C:26](=[O:29])[CH3:27])[CH3:22])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:25]
Reactant: CN[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: CC(=O)O
Product: CC(=O)N(C)[C@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 2-chloro-4-[(5-{[(2R)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol (obtained as described in Example 54, preparation of starting materials) to give N-[(1R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide in 100% yield; Mass spectrum MH+ 401.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:22]=[C:23]([CH:49]=[CH:50][CH:51]=2)[C:24]([NH:26][C:27]2[CH:28]=[C:29]([CH:45]=[CH:46][C:47]=2[CH3:48])[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:34]=2)=[O:31])=[O:25])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:48][C:47]1[CH:46]=[CH:45][C:29]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[CH:34]=2)=[O:31])=[CH:28][C:27]=1[NH:26][C:24](=[O:25])[C:23]1[CH:49]=[CH:50][CH:51]=[C:21]([O:20][CH:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)[CH:22]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCNC2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (0.6 ml) was added to a stirred solution of 3-[3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamido]-4-methyl-N-(3-morpholinophenyl)benzamide (0.3 g) in methylene chloride (6 ml) which had been cooled to 0° C. The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was triturated under diethyl ether to give the title compound, as its trifluoroacetate salt. The solid so obtained was dissolved in water (15 ml) and basified by the addition of potassium carbonate. The resultant precipitate was collected, washed with water and dried under vacuum to give the title compound (0.18 g); NMR Spectrum: (DMSOd6) 1.76 (m, 1H), 2.02 (m, 1H), 2.23 (s, 3H), 2.83 (ml, 2H), 3.06 (m, 5H), 3.55 (m, 1H), 3.76 (t, 4H), 4.98 (m, 1H), 6.62 (d, 1H), 7.12 (m, 2H), 7.31 (d, 1H), 7.4 (m, 3H), 7.52 (m, 2H), 7.78 (d, 1H), 7.99 (s, 1H), 10.07 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M+H+ 501.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O>[C:1]1([C:7](=[N:14][CH:15]([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Brc1cnccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cnccn1
Temperature: 110 °C

Procedure:
A mixture of ethyl 2-((diphenylmethylene)amino)acetate (6.0 g, 22.47 mmol), 2-bromopyrazine (7.1 g, 44.90 mmol), potassium carbonate (9.30 g, 67.40 mmol) and tetrabutyl ammonium iodide (8.10 g, 22.40 mmol) in N-methyl-2-pyrrolidone (25 mL) was heated in a sealed tube at 110° C. for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were washed with brine (25 mL) and dried over sodium sulfate. Removal of solvent under vacuum afforded crude product which was purified in Combi-Flash instrument using a gradient of methanol in chloroform. Yield: 4.90 g (63%). 1H NMR (300 MHz, DMSO-d6) δ: 1.16 (t, 3H), 4.07 (q, 2H), 5.26 (s, 1H), 7.18 (dd, 2H), 7.38-7.61 (m, 8H), 8.56 (d, 1H), 8.57 (d, 1H), 8.60 (s, 1H). MS (ES) MH+: 346.3 for C21H19N3O2.