Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[OH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[OH:18][C:19]1[CH:24]=[C:23]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: OB(O)c1cccc(O)c1
Product: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from 4-chloro-8-(trifluoromethyl)quinoline-3-carbonitrile and 3-hydroxyphenylboronic acid according to the procedure of Example 1. HRMS: calcd for C17H9F3N2O+H+, 315.07397; found (ESI, [M+H]+), 315.0752.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][C:21]#[CH:22])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:8][CH2:7]1.[C:33]([OH:42])(=[O:41])[C@@H:34]([C@H:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35]>C(O)C>[C:38]([CH:36]([CH:34]([C:33]([OH:42])=[O:41])[OH:35])[OH:37])([OH:40])=[O:39].[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:13]2/[C:14]([NH:19][CH2:20][C:21]#[CH:22])=[N:15][C:16](=[O:18])[S:17]/2)[CH2:10][CH2:11]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Solvent: CCO
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (1 g) in ethanol (15 mL) was added L-(+)-tartaric acid (0.32 g). The reaction mixture was stirred at 60° C. for 20 min, the solvent was evaporated under reduced pressure, and the residue was recrystallized from 2-propanol/heptane to give the title compound (1.14 g).
Reaction SMILES: [Na][Na].[P:3]([CH2:7][NH:8][CH2:9][C:10]([OH:12])=[O:11])([OH:6])([OH:5])=[O:4].[CH:13]1[C:18]([C:19]([C:21]2[CH:26]=[CH:25][C:24]3[C:27]([O:29][C:30](=[O:31])[C:23]=3[CH:22]=2)=[O:28])=[O:20])=[CH:17][C:16]2[C:32]([O:34][C:35](=[O:36])[C:15]=2[CH:14]=1)=[O:33].[OH2:37]>>[C:30]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[C:27]([OH:37])=[O:28])[C:19]([C:18]1[CH:17]=[C:16]([C:32]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][P:3]([OH:6])([OH:5])=[O:4])=[O:33])[C:15](=[CH:14][CH:13]=1)[C:35]([OH:34])=[O:36])=[O:20])([OH:29])=[O:31]
Reactant: O
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: O=C(c1ccc2c(c1)C(=O)OC2=O)c1ccc2c(c1)C(=O)OC2=O
Agent: [Na][Na]
Product: O=C(O)CN(CP(=O)(O)O)C(=O)c1cc(C(=O)c2ccc(C(=O)O)c(C(=O)O)c2)ccc1C(=O)O

Procedure:
To a 0.02 mole portion of the disodium salt of N-phosphonomethylglycine, prepared as described in previous examples, there is added 3.2 grams (0.01 mole) of 3,3',4,4'-benzophenonetetracarboxylic dianhydride. A pH of about 8 is maintained with periodic additions of alkali, and further anhydride, in 3.2 grams and 1.0 gram portions, are added to complete the reaction. The reaction mixture is diluted with water and passed through a column of ion exchange resin in the acid form. The second and third 20 ml. cuts are combined and dried to yield 4-(3',4-dicarboxybenzoyl)-N-carboxymethyl-N-(phosphonomethyl)phthalamic acid (in the monohydrate form) as a tan glass. Elemental analysis gives 44.18% carbon, 3.47% hydrogen, 2.77% nitrogen and 6.12% phosphorus as against calculated values of 45.55%, 3.44%, 2.66% and 5.87% for C20H16NO13P.H2O. ##STR22##
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[C:10]([CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]1)=[C:9]2[C:41]([OH:43])=O)(=[O:5])=[O:4])[CH3:2].[F:44][C:45]([F:55])([F:54])[C@@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH2:47].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1)[C:10]([CH2:28][N:29]1[CH2:30][CH2:31][CH:32]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[CH2:33][CH2:34]1)=[C:9]2[C:41]([NH:47][C@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:45]([F:44])([F:54])[F:55])=[O:43])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cc2c(C(=O)O)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCS(=O)(=O)c1cc2c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c(CN3CCC(N4CCOCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.303 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.069 g, 0.393 mmol), N,N-diisopropylethylamine (10.57 μL, 0.061 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.252 mL as a 50% solution in ethyl acetate, 0.424 mmol) in dichloromethane (2 mL) was stirred at 0° C. for 2 h, then warmed to room temperature overnight. The solution was diluted with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.166 g, 67% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.79 (br. s., 1H), 8.78 (s, 1H), 7.81 (s, 1H), 7.76-7.80 (m, 1H), 7.65-7.69 (m, 2H), 7.60 (s, 1H), 7.53-7.59 (m, 2H), 7.42-7.49 (m, 3H), 6.20-6.31 (m, 1H), 4.11 (s, 3H), 3.65-3.71 (m, 4H), 3.54-3.65 (m, 2H), 3.47 (q, J=7.28 Hz, 2H), 2.59-2.71 (m, 1H), 2.38-2.46 (m, 4H), 2.17-2.28 (m, 1H), 2.04 (t, J=11.04 Hz, 1H), 1.49-1.65 (m, 6H), 1.32 (t, J=7.53 Hz, 3H); MS (m/z) 779.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:11]=3)[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:76][C:77]1[CH:78]=[CH:79][C:80]2[N:81]([C:83]([SH:86])=[N:84][N:85]=2)[N:82]=1>CN(C=O)C.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]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:86][C:83]2[N:81]4[N:82]=[C:77]([CH3:76])[CH:78]=[CH:79][C:80]4=[N:85][N:84]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2)cn1
Reactant: Cc1ccc2nnc(S)n2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A solution of trifluoro-methanesulfonic acid 3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl ester (15.9 g, 44.79 mmol), diisopropylethylamine (15.5 mL, 89.58 mmol) in DMF (150 mL) under nitrogen was degassed by bubbling with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium (2.0 g, 2.24 mmol, Strem catalyst) and Xantphos (2.54 g, 4.48 mmol) were added together in one portion, followed by 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (7.44 g, 44.79 mmol) under a stream of nitrogen. The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was filtered while hot and the filtrate was cooled to precipitate. The solid was collected and washed with methanol to give an off-white solid, which was purified via column chromatography to get 13.3 g of 3-(1-methyl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (79% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:15]=[C:16]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[CH:17]=[CH:18][C:19]=2[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[ClH:39]>ClCCl.CO.C(OCC)C>[ClH:39].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[CH:15]=[C:16]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)[CH:17]=[CH:18][C:19]=2[C:20](=[O:25])[C:21]([F:22])([F:24])[F:23])[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(OC)cc(C(C)Nc2cc(N3CCNCC3)ccc2C(=O)C(F)(F)F)c1
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of t-butyl 4-(3-(1-(3,5-dimethoxyphenyl)ethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (231 mg, 0.43 mmol) in dichloromethane (2.0 mL) and methanol (0.5 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 3 hours. The solvent was removed by rotary evaporation to afford the title compound (198 mg, 97% yield). 1H NMR (400 MHz, CD3OD): δ 7.62 (m, 1H), 6.52 (s, 2H), 6.36 (m, 2H), 5.49 (s, 1H), 4.66 (m, 1H), 3.57 (m, 2H), 3.50 (m, 2H), 3.21 (m, 4H), 1.58 (d, 3H); MS (ESI) m/z: Calculated for C22H27F3N3O3: 438.2; Observed: 439.5 (M++1) [corresponding to the free base].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:7]=1[C:8]([NH2:10])=[O:9].[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1.C(OCC)(=O)C>[F:15][C:13]1[CH:14]=[C:6]([O:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([NH:1][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])[CH:3]=2)[C:7]([C:8]([NH2:10])=[O:9])=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[CH:12]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1cccc(N)c1
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
In analogy to GP 6b, 144 mg of 2-(3-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Intermediate 1.4; 0.3 mmol, 1 eq.) were dissolved in 1.5 mL pyridine and treated with 51 mg iso-propylsulfonyl chloride (0.36 mmol, 1.2 eq., dissolved in 0.5 mL pyridine). The reaction mixture was stirred at rt overnight, treated with another 0.5 eq. sulfonylchloride (in 0.2 mL pyridine) and stirring was continued at rt overnight. After addition of further 0.5 eq. sulfonylchloride (in 0.2 mL pyridine) and further stirring at rt overnight, the resulting mixture diluted with ethyl acetate, washed with water and the organic layers dried. Concentration in vacuo followed by HPLC purification provided 82 mg (46% yield) of the desired compound, which includes substoichiometric amounts of formic acid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(CC)CC.Cl[C:20]([O:22][CH3:23])=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:20](=[O:21])[O:22][CH3:23])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(Br)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Nc1ccc([N+](=O)[O-])c(Br)n1
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 6-bromo-5-nitropyridin-2-amine (1.4 g, 10 mmol), Et3N (2.0 g, 20 mol) and DMAP (70 mg) in CH2Cl2 (20 mL) was added ClCO2Me (1.3 g, 10 mmol) drop-wise at 0° C. The mixture was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 6-bromo-5-nitropyridin-2-ylcarbamate (1.4 g, 82%). 1H NMR (400 MHz, DMSO) δ 10.78 (brs, 1H), 8.56 (d, J=9.2 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 3.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH:18]=O.CC(OC)(C)C.C([BH3-])#N.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:4]=1
Reactant: CN(C)CCOc1cc(N)ccc1Cl
Reactant: COC(C=O)OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(CNc1ccc(Cl)c(OCCN(C)C)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 4-chloro-3-(2-dimethylaminoethoxy)aniline (D6, 1.22 g, 0.006 mol) in McOH (30 ml) containing dimethoxyethanal in MTBE (1.76 g, 0.17 mol) and glacial acetic acid (1.71 g) was added sodium cyanoborohydride (1.78 g, 0.03 mol) portionwise at 0 C. After addition, the reaction was left to stir at room temperature for 1 hour, and then 10% aqueous NaOH was added and the mixture was extraced with CH2Cl2 and the combined organic layers were dried (Na2SO4), and concentrated in vacuo to give a brown oil. Purification by FCC, eluting with CH2Cl2 gave the title compound (1.49 mg, 87% )
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:11][N:12]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:13]([CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[CH:3]=1)[CH3:14]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: CCOc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cncc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)c1
Temperature: 82.5 °C
Yield: 88.8 %

Procedure:
Under a nitrogen atmosphere, a mixture of 5-bromo-3-ethoxypyridine (1.20 g, 5.94 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.18 g, 5.94 mmol), palladium(II) acetate (13.5 mg, 0.06 mmol), tri-o-tolylphosphine (73.1 mg, 0.24 mmol), triethylamine (1.5 mL, 10.8 mmol), and anhydrous acetonitrile (3 mL) was stirred and heated under reflux at 80-85° C. for 28 h. The resulting mixture, containing beige solids, was cooled to ambient temperature, diluted with water (20 mL), and extracted with CHCl3 (3×20 mL). The combined light-yellow CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried producing a yellow oil (1.69 g). The crude product was purified by column chromatography on silica gel (100 g), eluting with ethyl acetate-hexane (1:1, v/v). Selected fractions containing the product (Rf 0.20) were combined, concentrated by rotary evaporation, and the residue was vacuum dried to give 0.67 g (35.2%) of a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH2:11]([N:13](CC)[CH2:14]C)C.CNC>ClCCl>[CH3:11][N:13]([CH3:14])[C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:9]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-pyridine-2-carbonyl chloride (1 eq) in dichloromethane was cooled to 0° C., whereupon triethylamine (2 eq) was added followed by dimethylamine (2 eq, 2M solution in THF). The solution was allowed to warm to room temperature and let stir overnight. It was then washed with 1M NaOH. The separated organic layer is dried over MgSO4, filtered, and concentrated to yield the desired product. HPLC, 1.82 min; MS: MH+=185.6
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])CC4)=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.ClC(N1CCNC1=O)=[O:30].CN1CCN(C(Cl)=O)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25][NH:24][C:27]4=[O:30])=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)N2CCC3(CC(C#Cc4cccc(Cl)c4)=NO3)C2)CC1
Reactant: O=C(Cl)N1CCNC1=O
Agent: CN1CCN(C(=O)Cl)CC1
Product: O=C1NCCN1C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Yield: 51.3 %

Procedure:
The title compound was synthesized using the method described for the compound of Example 104, replacing 1-chlorocarbonyl-2-imidazolidinone for by 4-methyl-1-piperazinecarbonyl chloride. After evaporation, the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient EtOAc-MeOH from 95:5 to 8:2) to afford a yellowish solid. Yield: 51.3%.
Reaction SMILES: Br[C:2]1(C(O)=O)[NH:6][CH:5]=[CH:4][S:3]1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([O-])([O-:18])=[O:17].[K+].[K+]>O1CCOCC1>[N:10]1([C:2]2[S:3][C:4]([C:16]([OH:18])=[O:17])=[CH:5][N:6]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: O=C(O)C1(Br)NC=CS1
Reactant: O=C([O-])[O-]
Reactant: C1CNCCN1
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1cnc(N2CCNCC2)s1

Procedure:
2-Bromothiazole carboxylic acid 1 (1 g; 4.8 mmol) and piperazine (6.2 g; 72 mmol; 24 equiv.) were dissolved in dioxane, K2CO3 (3.32 g; 24 mmol; 5 equiv.) was added and the suspension was refluxed over night. The solvent was removed at the rotary evaporator, the residue dissolved in ethanol, filtered and recrystallized. The crude product was dried at the oil pump and directly used in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].CO.[NH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O-:8])=[O:7].[NH4+:14]
Reactant: N
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CO
Product: Nc1cc(Cl)ccc1C(=O)[O-]
Product: [NH4+]
Reaction time: 2 h
Yield: 95 %

Procedure:
In a 50 mL volume glass vessel equipped with a stirrer and a thermometer were placed 5.0 g (29.1 mmol) of 4-chloroanthranilic acid and 20 mL (156 mmol) of 15 wt. % ammonia methanol solution. The reaction was carried out for 2 hours at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, to obtain 5.0 g (isolated yield: 95%) of ammonium 4-chloroanthranilate as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[I:17].N(OC(C)(C)C)=O.[Si]([N:29]=[N+:30]=[N-])(C)(C)C>CC#N>[N:1]([C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[I:17])=[N+:29]=[N-:30]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)c(I)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1ccc(N=[N+]=[N-])c(I)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
tert-Butyl 4-amino-3-iodobenzylcarbamate (1.0 g, 2.87 mmol) was dissolved in CH3CN (6.0 ml). The solution was cooled to 0° C., tert-butyl nitrite (444.3 mg, 4.30 mmol) and TMS azide (397.1 mg, 3.45 mmol) were added. The mixture was then stirred at r.t for 2.0 h. The solvents were removed under vacuum and the residue purified by flash chromatography (Pet. Ether/EtOAc 85:15) affording 936 mg (87%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=O.[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:14]=1[C:15]#[N:16].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33]C[C@@H:31]([NH2:35])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[Br:21][C:18]1[CH:17]=[C:14]2[C:13](=[CH:20][CH:19]=1)[N:12]=[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[OH:2])[N:16]=[C:15]2[NH:35][C@H:31]1[CH2:33][CH2:34][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:28])[CH2:30]1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: N#Cc1cc(Br)ccc1N
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(Br)cc23)C1

Procedure:
The title compound was prepared from 2-methoxybenzoyl chloride, 2-amino-5-bromobenzonitrile, and (R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester using methods analogous to those described in Synthesis 1, steps 1A, 1B, and 1D.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=O)[C:5]=12.P(Cl)(Cl)([Cl:18])=O.O.[OH-].[NH4+]>C(Cl)Cl>[Cl:18][C:6]1[C:5]2=[CH:1][CH:2]=[CH:3][N:4]2[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1
Reactant: O=C1Nc2ccccc2Cn2cccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: ClC1=Nc2ccccc2Cn2cccc21
Temperature: 25 °C

Procedure:
A slurry of 881 g of 10,11-dihydro-5-H-pyrrolo-[2,1-c][1,4]benzodiazepin-11-one is stirred in 12 L of methylene chloride, and 819 g of 99% phosphorus oxychloride is added all at once. The mixture is stirred and refluxed for 19 hours. The reaction mixture is cooled to room temperature. A mixture of 5 L of crushed ice, 7.5 L of cold water and 1.81 kg of 28% ammonium hydroxide solution is stirred and 1.25 L portions of the reaction mixture are added over a period of 15 minutes. The reaction temperature is kept below 25° during the addition. After stirring for 15 minutes, the layers are separated, the methylene chloride layer is washed by stirring with 1 L of cold water then dried by stirring with magnesium sulfate for 1 hour. Charcoal (90 g) is added and the mixture is filtered through filter-cel. The methylene chloride solution is concentrated to dryness in vacuo to give 11-chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, m.p. 102°-104°.
Reaction SMILES: [CH2:1]([O:5][P:6]([CH3:8])[OH:7])[CH2:2][CH2:3][CH3:4].[C:9](=[O:16])([O:11][CH2:12][C:13](=[CH2:15])[CH3:14])[NH2:10].C1C(C(OOC(C)(C)C)=O)=CC=CC=1>>[CH2:1]([O:5][P:6]([CH2:14][CH:13]([CH3:15])[CH2:12][O:11][C:9](=[O:16])[NH2:10])([CH3:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOP(C)O
Reactant: C=C(C)COC(N)=O
Agent: CC(C)(C)OOC(=O)c1ccccc1
Product: CCCCOP(C)(=O)CC(C)COC(N)=O
Reaction time: 1 h
Yield: 95 %

Procedure:
In a nitrogen atmosphere 100 g of methane-phosphonous acid mono-n-butyl ester are heated to 140° C. while stirring. Over a period of 2 hours a mixture of 85 g of methallyl carbamate and 3.7 g of tert.butyl perbenzoate is added dropwise and stirring is continued for 1 hour at 135° C. Distillation is then started up to an internal temperature of 140° C. and at 0.8 torr, whereby about 5 g of distillate are obtained. 180 g of (3-carbamoyloxy-2-methyl-propyl)methyl-phosphinic acid n-butyl ester are obtained, ND23 : 1.4725, corresponding to a yield of about 95% of the theory. ##STR7##