Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:41])[NH2:40])=[CH:35][CH:34]=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:40])[NH:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Product: CCOC(=O)CN(c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 31 from 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and benzoyl chloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: C1CNCCN1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Solvent: CC#N
Product: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Yield: 87.8 %

Procedure:
A solution of 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide (2.52 g, 11.0 mmol) and piperazine (2.83 g, 32.8 mmol) in acetonitrile (30 mL) was heated to refluxed for 2 hours. The solvent was removed by evaporation, the residue was dissolved in water (50 mL) and extracted with dichloromethane (3×100 mL). The organic extract was dried over anhydrous Na2SO4 and then evaporated. The residue was passed through a pad of silica gel and concentrated to give 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (2.68 g, 88% yield). MS (ES+) m/z 278 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][NH:5][N:4]=1.Cl[CH2:14][C:15]1[NH:16][C:17](=[O:25])[C:18]2[CH:23]=[C:22]([CH3:24])[S:21][C:19]=2[N:20]=1.CC(C)([O-])C.[K+]>C1COCC1>[OH:10][CH2:9][CH2:8][C:7]1[C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][N:5]([CH2:14][C:15]2[NH:16][C:17](=[O:25])[C:18]3[CH:23]=[C:22]([CH3:24])[S:21][C:19]=3[N:20]=2)[CH:6]=1
Reactant: OCCc1c[nH]nc1C(F)(F)F
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CCO)c(C(F)(F)F)n3)nc2s1
Temperature: 75 °C
Yield: 32 %

Procedure:
A mixture of 2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)ethanol (50 mg, 0.278 mmol), 2-(chloromethyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (60 mg, 0.278 mmol) and potassium tert-butoxide (62 mg, 0.07 mL, 0.555 mmol) in THF (3 mL) was heated to 75° C. for 4 h. The reaction mixture was allowed to cool to RT before being filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound as a white solid (32 mg, 0.089 mmol, 32%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]O)=[CH:18][CH:17]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:45]N1C(=O)CCC1=O>C(Cl)Cl>[Br:45][CH2:24][CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:3]([CH2:1][CH3:2])[C:11]3[C:6]([C:5]=2[C:14]#[N:15])=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)=[CH:17][CH:18]=1
Reactant: CCn1c(-c2ccc(OCCO)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCn1c(-c2ccc(OCCBr)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
1-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-phenyl]-1H-indole-3-carbonitrile (450 mg, 1.34 mmol), prepared as in example 1AZ, is combined with PPh3 (878 mg, 3.35 mmol) in CH2Cl2 (32 mL) at 0° C. N-bromosuccinimide (600 mg, 3.37 mmol) is added in one portion. The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is washed with aqueous NaHCO3. The organic layer is dried and concentrated, and purified by silica gel chromatography (CH2Cl2) to yield 2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (506 mg, 95%), compound 253 as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1ccc(O)cc1Br
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(C)c(Br)cc1O
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To 3-bromo-4-methylphenol (2 g, 10.69 mmol) was added acetyl chloride (0.80 ml, 11.23 mmol). The mixture was heated at 60° C. for one hour, cooled and aluminium chloride (1.426 g, 10.69 mmol) was added. The mixture was heated at 180° C. for 40 minutes, cooled and quenched by stirring with 5N HCl (20 ml) for 20 minutes. The solid was filtered to yield the title compound as a brown solid. 2.45 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][Si](C)(C)C)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:18])[CH:3]=1>CN(C=O)C.[Cu]I>[Cl:18][C:4]1[CH:3]=[C:2]2[C:11]([CH:12]=[CH:13][NH:1]2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc[nH]c2cc1Cl
Temperature: 110 °C

Procedure:
A mixture of compound 23e (0.532 mmol, 150 mg) and CuI (0.32 mmol, 60 mg) in DMF (1.5 mL) was heated at 110° C. for 5 h and then cooled to room temperature. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 23f.
Reaction SMILES: CC1[N:3]=[C:4]2[C:9]([CH3:10])=[C:8]([C:11]3[O:12][C:13]([N+]([O-])=O)=[CH:14][CH:15]=3)[N:7]=[C:6]([NH2:19])[N:5]2N=1.C([NH:24]C1NC(=O)C(C)=C(C2OC=CC=2)N=1)(=O)C.O.NN>>[NH2:19][C:6]1[N:7]=[C:8]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:9]([CH3:10])=[C:4]([NH:3][NH2:24])[N:5]=1
Reactant: Cc1nc2c(C)c(-c3ccc([N+](=O)[O-])o3)nc(N)n2n1
Reactant: CC(=O)Nc1nc(-c2ccco2)c(C)c(=O)[nH]1
Agent: NN
Solvent: O
Product: Cc1c(NN)nc(N)nc1-c1ccco1

Procedure:
1-methyl-2-[2,8-dimethyl-7-(5-nitro-2-furyl)-s-triazolo[2,3-c]pyrimidinyl-5-]-imino-pyrrolidine (m.p. 244° - 246°C.) from the N-methyl-pyrrolidone-(2)-phosphorus oxychloride adduct and 2,8-dimethyl-5-amino-7-(5-nitro-2-furyl)-s-triazolo[2,3-c]pyrimidine; the latter compound (m.p. 290° - 295°C.) used as starting material was obtained by chlorinating 2-acetamido-4-(2-furyl)-5-methyl-6(1H)-pyrimidinone and the intermediate obtained (m.p. 155° - 160°C.) reacted with hydrazine hydrate to give 2-amino-4-(2-furyl)-6-hydrazino-5-methyl-pyrimidine (m.p. 220° - 222°C.) which was cyclised with orthoacetic acid triethyl ester, the intermediate obtained then nitrated to give 5-amino3,8-dimethyl-7-(5-nitro-2-furyl)-s-triazolo[4,3-c]pyrimidine (m.p. 290°C.; decomp.) which was heated in ethanol saturated with hydrogen chloride;
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O.O>[N:13](=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)[OH:14]
Reactant: O=C1CCCc2cccnc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2cccnc21
Yield: 79.7 %

Procedure:
A solution of 2.22 g of 8-oxo-5,6,7,8-tetrahydroquinoline, 2.1 g of hydroxylamine hydrochloride, and 4.1 g of sodium acetate in 15 mL of 3:1 ethanol-water was heated at 70° C. for 1 h. The reaction mixture was then diluted with water and extracted with dichloromethane. Evaporation of the extracts gave 1.95 g of product which was pure enough by NMR to be used in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=3)[S:10][C:3]=12.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].C([O-])([O-])=O.[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.ClCCl>[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:32][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=3)[S:10][C:3]=12
Reactant: CCOC(=O)Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 185 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A suspension of 373 (1.05 g, 3.26 mmol), 2-fluoro-4-nitrophenol (1.10 g, 7.00 mmol), and K2CO3 (2.0 g, 15 mmol) in diphenyl ether (10 mL) was heated with stirring to 185° C. for 3 h. The mixture was cooled, diluted with dichloromethane, filtered, and the filtrate was concentrated. Silica gel chromatography (75% ethyl acetate/hexanes) of the residue provided 374 (0.98 g, 68% yield). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.52 (d, J=5.3, 1H); 8.46 (dd, J=10.4, 2.5, 1H); 8.20-8.17 (m, 1H); 7.89 (d, J=1.2, 1H), 7.77-7.74 (m, 1H); 7.75 (s, 1H); 7.69 (t, J=8.2, 1H); 6.86 (d, J=5.3, 1H); 5.04 (s, 2H); 4.17 (q, J=7.2, 2H); 1.22 (t, J=7.2, 3H). LRMS (M+H): 442.9.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ncnc2sccc12
Solvent: CN(C)C=O
Product: Clc1ncnc2sccc12
Temperature: 25 °C

Procedure:
A mixture of thieno[2,3-d]pyrimidin-4-ol derivative 3 (3.7 mmol), thionyl chloride (5.5 mL) and dry DMF (0.5 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and the excess thionyl chloride was removed by vacuum distillation. To the resulting residue 200 g of ice was added and extracted with dichloromethane (3×100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The product was purified by silica chromatography (100% DCM) to afford 4-Chloro-thieno[2,3-d]-pyrimidine 4 in 80-95% yields.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:23][CH2:22][N:21]3[C:14](=[CH:15][C:16]4[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=43)[C:13]2=[O:26])=[CH:10][CH:9]=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:43]3[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B4OC(C)(C)C(C)(C)O4)[CH:48]=3)=[N:40][CH:41]=2)[CH2:32][CH2:31]1)[CH3:29].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:43]3[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47]([C:7]4[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:11]([N:12]5[CH2:23][CH2:22][N:21]6[C:14](=[CH:15][C:16]7[CH2:17][C:18]([CH3:24])([CH3:25])[CH2:19][C:20]=76)[C:13]5=[O:26])[CH:10]=[CH:9][CH:8]=4)[CH:48]=3)=[N:40][CH:41]=2)[CH2:32][CH2:31]1)[CH3:29]
Reactant: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CCN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(-c4cccc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, bromide 167f (150 mg, 0.348 mmol), 190a (306 mg, 0.696 mmol), Pd(PPh3)4 (40.2 mg, 0.0348 mmol), Na2CO3 aqueous solution (1.0 N, 1.15 mL, 1.15 mmol), DME (4 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 190b.
Reaction SMILES: O.COC1C=CC(C[O:11][C@@H:12]([C@@H:54]([CH3:64])[CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@H:13]([C@H:15]([O:46][Si:47]([CH3:53])([CH3:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:16]([CH3:45])[CH2:17]/[C:18](/[CH3:44])=[CH:19]\[C@H:20]([CH3:43])[C@H:21]([C@@H:30]([CH3:42])[CH2:31][O:32]CC2C=CC(OC)=CC=2)[O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:14])=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[CH3:25][C:24]([Si:23]([CH3:28])([CH3:29])[O:22][C@H:21]([C@@H:20]([CH3:43])/[CH:19]=[C:18](/[CH3:44])\[CH2:17][C@H:16]([CH3:45])[C@@H:15]([O:46][Si:47]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:52])[CH3:53])[C@H:13]([CH3:14])[C@@H:12]([OH:11])[C@@H:54]([CH3:64])[CH2:55][O:56][CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C@@H:30]([CH3:42])[CH2:31][OH:32])([CH3:27])[CH3:26]
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](OCc2ccc(OC)cc2)[C@@H](C)COCc2ccccc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: C/C(=C/[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CO)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](O)[C@@H](C)COCc1ccccc1
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
Water (3 mL) is added to a solution of (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S)-2-[(4-methoxyphenyl)methoxy]-1,3-dimethyl-4-(phenylmethoxy)butyl]-5-[(1S)-2-[(4-methoxyphenyl)methoxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadec-7-ene (1.0 g, 1.19 mmol) in CH2Cl2 (30 mL) at 23° C. and stirred for 5 min. DDQ (1.62 g, 7.14 mmol, 6 eq) is added at once and stirred for 15 min. The product mixture is concentrated. The residue is filtered through celite and washed with hexane. The hexane layers are dried and concentrated. The crude product is chromatographed (from hexane to 10% EtOAc in hexane) to give 630 mg (89%) of the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:38]([CH2:42][C:43](Cl)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:8][CH:7]=1)[C:43](=[O:44])[CH2:42][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: CC(C)(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC(=O)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-amine (0.100 g, 0.232 mmol) and triethylamine (0.100 mL, 0.696 mmol) in 2 mL methylene chloride was added tert-butylacetyl chloride (0.081 mL, 0.58 mmol) dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 529.2 (M+1)+
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.C[Si](C)(C)[O:41][NH2:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[OH:41][NH:42][C:36]([CH:32]([NH:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:12]([C:4]3[NH:3][C:2](=[O:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[O:13])[CH:17]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30])[CH:33]([CH3:34])[CH3:35])=[O:37]
Reactant: C[Si](C)(C)ON
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
A suspension of N-{[3′-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)biphenyl-4-yl]sulfonyl}valine obtained in Example 77 (0.080 g, 0.150 mmol), O-(trimethylsilyl)hydroxylamine (0.055 mL, 0.449 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (0.086 g, 0.449 mmol) and 1-hydroxybenzotriazole (0.061 g, 0.449 mmol) in DMF (5 mL) was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, and washed successively with 0.05N hydrochloric acid, aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol-diethyl ether to give the title compound as a white powder (0.058 g, 71%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:17]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=1.CO.Cl.O1CCOCC1>>[NH2:17][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][Si:13]([CH3:15])([CH3:14])[CH3:16])[CH:6]=1)[CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc(C#C[Si](C)(C)C)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[Si](C)(C)C#Cc1cccc(C[C@H](N)CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
tert-Butyl ((1S)-2-hydroxy-1-{3-[(trimethylsilyl)ethynyl]benzyl}ethyl)carbamate (0.84 g, 2.4 mmol), methanol (2.0 mL, 49 mmol), and 4.0 M hydrogen chloride in dioxane (5.0 mL, 20 mmol) were mixed together and stirred at room temperature for 1 h. The solvent was removed under vacuum to give 0.61 g (98% yield) of the desired product. LC-MS found: 248.0 (m+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:18](=[O:20])=[O:19].Cl>C1COCC1>[Br:1][C:2]1[C:3]([C:18]([OH:20])=[O:19])=[C:4]([F:9])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Br)c(C(=O)O)c1F
Reaction time: 1.17 h
Yield: 49.2 %

Procedure:
50 ml (0.385 mol) of 4-bromo-2-fluorotoluene were dissolved in 750 ml of THF, and 231 ml (0.462 mol) of a 2 M solution of LDA in THF were added dropwise at −70° C. After 70 minutes, 37.2 g (0.846 mol) of carbon dioxide were passed in, and the batch was allowed to thaw. After acidification using conc. hydrochloric acid, the solution was extracted with MTB ether, and the combined organic phases were washed with water, dried over sodium sulfate and evaporated under reduced pressure. Crystallisation of the crude product from 1-chlorobutane gave 44.1 g (49%) of 6-bromo-2-fluoro-3-methylbenzoic acid as white crystals.
Reaction SMILES: [OH-].[K+].[N+:3]([CH2:6][CH3:7])([O-:5])=[O:4].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].Cl>O.CS(C)=O>[N+:19]([C:10]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=1[CH:6]([N+:3]([O-:5])=[O:4])[CH3:7])([O-:21])=[O:20]
Reactant: CC[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 19 °C

Procedure:
Potassium hydroxide pellets (8.42 g; 0.150 mol; 3 equiv) were crushed and placed in a 250-mL 3-necked flask equipped with a thermometer and an addition funnel. Reagent-grade DMSO (25 mL) was added and the mixture vigorously stirred. An ice-water cooling bath was then applied and when the temperature of the reaction mixture had cooled to 19° C. a mixture of nitroethane (3.95 mL; 0.055 mol; 1.1 equiv) and 4-chloro-3-nitrobenzotrifluoride (1; 7.46 mL; 0.050 mol) were added to the reaction mixture (addition funnel) over 15 min at a rate such that a temperature of 15-20° C. was maintained. After the addition was complete, the reaction mixture was cooled to 15° C. and the ice bath was replaced with a cool water bath (10-15° C.) and the reaction mixture was allowed to warm to 20° C. over 2 h, at which time GC analysis indicated >98% consumption of 1 and a ratio of 2:3 of 98:2. Toluene (25 mL) was added and the reaction mixture was cooled in ice-water. Aqueous hydrochloric acid (6 N; 15 mL; 0.090 mol) was added dropwise with vigorous stirring at such a rate that the temperature remained below 20° C. Water (40 mL) was then added and the layers were allowed to separate for 10 min. The bottom aqueous layer was decanted, and the top organic solution was used directly for the next step. An aliquot of this organic solution was analyzed by 1H NMR and indicated a 96:4 ratio of 2:3. 2: 1H NMR (CDCl3) δ 8.349 (s, 1H); 7.976 (dd, 1 H, J=1.71, 8.24 Hz); 7.788 (d, 1H, J=8.24 Hz); 6.296 (q, 1H, J=6.96 Hz); 2.036 (d, 3H, J=6.78 Hz). GC (30 m DB-17, 100° C., 3 min; 100-280° C., 15/min; 280° C., 1 min): tR 10.71 min 3: 1H NMR (CDCl3) δ 10.815 (s, 1H); 8.435 (d, 1H, J=1.77 Hz); 7.830 (dd, 1H, J=2.19, 8.79 Hz); 7.315 (d, 1H, J=8.91 Hz). GC (30 m DB-17, 100° C., 3 min; 100-280° C., 15°/min; 280° C., 1 min): tR 5.53 min.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O-:25])(=[O:24])[CH:22]=[CH2:23].[K+].C1(C=CC(O)=CC=1)O>CN(C)C=O>[C:21]([O:25][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)[O-]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1 mole triphenylchloromethane was stirred with 1.5 moles potassium acrylate in 998 g dimethyl formamide in the presence of 0.14 g hydroquinone under the conditions described in Example 1. The precipitated potassium chloride was filtered off and the triphenyl methyl acrylate solution was concentrated by rotary evaporation at 65° to 100° C. and reduced to produce liquid triphenylmethyl acrylate. This was dissolved at 70 percent in xylene and filtered.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2([C:15]([O:17]CC)=[O:16])[CH2:14][CH2:13]2)=[O:10])[CH:6]=[N:5][CH:4]=1.C(O)(=O)C>CO>[N:3]1[CH:8]=[C:7]([C:9]([NH:11][C:12]2([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[O:10])[CH:6]=[N:5][CH:4]=1
Reactant: CCOC(=O)C1(NC(=O)c2cncnc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NC1(C(=O)O)CC1)c1cncnc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
65 mL of a 2N sodium hydroxide solution were added to a solution of 11.0 g (46.76 mmol) of ethyl 1-[(pyrimidine-5-carbonyl)amino]-cyclopropanecarboxylate in 200 mL methanol and the mixture was stirred for one hour at 50° C. Then it was neutralised with concentrated acetic acid and evaporated to dryness in vacuo. The crude product thus obtained was purified by chromatography.