Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCC[C@@H](O)CC(N)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC[C@H](CC(N)=O)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-hydroxyhexadecanamide (100 mg) and pyridine (210 μl) in dichloromethane (10 ml) was added methanesulfonyl chloride (144 μl). This mixture was stirred at room temperature overnight, and the resulting precipitate was filtered off. The filtrate was concentrated, and dissolved in ethyl acetate (20 ml). This solution was washed with 1N-hydrochloric acid (20 ml×3), saturated sodium carbonate (20 ml×2), and brine (20 ml). After drying over MgSO4 and concentration, the residue was chromatographed on a silica gel, eluting with a mixture of dichloromethane and methanol (50:1) to give (R)-3-methanesulfonyloxyhexadecanamide (40 mg).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH:40]3[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]3)=[CH:39][C:34]=2[O:33][CH2:32]1>>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH:40]3[CH2:45][CH2:44][CH:43]([N:8]4[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]5[C:20]6[CH:21]=[C:22]([O:25][C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:24][C:19]=6[O:18][N:17]=5)[CH2:11]4)[CH2:42][CH2:41]3)=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: O=C(CNc1noc2ccc(OC(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1noc2ccc(OC(F)(F)F)cc12)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethoxy-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:32]=O>C(O)C.N1CCCCC1>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[CH:21][NH:20][C:19]=1[CH:32]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.1 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (40.6 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:16])=[C:11]([NH2:15])[CH:12]=2)[CH2:7][N:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4].O.C(=O)(O)[O-].[Na+].Cl[CH:30]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)=[CH:36][CH:35]=1)[C:31](Cl)=[O:32]>CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:10]([O:16][C@@H:30]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=5)=[CH:36][CH:35]=4)[C:31](=[O:32])[NH:15]3)=[CH:9][C:8]=2[CH2:7][N:6]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: O=C(Cl)C(Cl)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: COC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-isopropyl ester 3-methyl ester (1.8 g) was dissolved in 10 mL EtOAc, 20 mL water and 5.0 g sodium bicarbonate added. 2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride in 10 mL of EtOAc was added and the mixture stirred at rt for 1.5 h. The organic layer was washed with brine, dried and evaporated. The residue was dissolved in 15 mL DMF and potassium carbonate (4.1 g) added. The mixture stirred at r.t. for 3 h and was poured onto water and EtOAc. The organic was washed with 1N HCl, dried and evaporated. The residue was purified over silica (hexanes-EtOAc-2M ammonia in MeOH) to provide (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester 7-methyl ester (2.0 g). LC-MS (m/z) 600.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]2=[O:21])[CH2:3]1
Reactant: O=C1Cc2ccccc2N1
Reactant: CC1CC(=O)c2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC1CC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 130 °C
Yield: 13.4 %

Procedure:
A mixture of 0.5 g of 3-methyl-1-indanone, 1.37 g oxindole and 5 ml piperidine in 3 ml of dimethylforamide was heated in a sealed tube at 130° C. overnight to yield a reddish-brown suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. Chromatography afforded 120 mg of 3-(3-methylindan-1-ylidene)-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=2)[CH3:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.CC(O)=O.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=2)[CH3:16])=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(N)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: CC(Oc1ccc(N)c2ccccc12)c1ccnc(N)c1
Yield: 98.6 %

Procedure:
A solution of 4-(1-(4-Nitronaphthalen-1-yloxy)ethyl)pyridin-2-amine (38) (91 mg, 0.294 mmol) in MeOH (15 mL) and AcOH (3.0 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm, 10% Pt/C Cat-Cart, full hydrogen mode). The volatiles were removed under reduced pressure, leaving a purple solid, which was then subjected to SCX capture and release to give the title compound (39) (81 mg, 99%) as a purple oil: m/z 280 (M+H)+ (ES+).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][N:8]([C:14]1[N:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:16]=[CH:17][N:18]=1)[N:7]=3.ClC1N(C2C=CC(F)=CC=2F)N=CN=1.[Br:43]C1C=CC2OCCC3C(=NNC=3)C=2C=1.C(OCC)(=O)C>C1CCCCC1>[Br:43][C:28]1[CH:2]=[CH:3][C:4]2[O:13][CH2:12][CH2:11][C:10]3[C:6](=[N:7][N:8]([C:14]4[N:15]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:16]=[CH:17][N:18]=4)[CH:9]=3)[C:5]=2[CH:27]=1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(Br)cc2OCC3)c(F)c1
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Agent: Fc1ccc(-n2ncnc2Cl)c(F)c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(Br)ccc2OCC3)c(F)c1
Yield: 62 %

Procedure:
9-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared similarly to 8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene from 5-chloro-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole (1.33 g, 6.16 mmol) and 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.36 g, 5.13 mmol), the crude product was subjected to flash chromatography (SiO2, gradient 0 to 35% ethyl acetate in cyclohexane) to give 9-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen (1.42 g, 62%). LCMS RT=4.80 M+H+=444/446.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][S:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: O=C(N1CCSCC1)N1CC(c2ccc(CC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
According to General Method 6A, 300 mg (0.720 mmol) of the compound from Example 45A and 79.3 mg (0.792 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted Yield: 160 mg (45% of theory)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C(=O)([O-])[O-].[K+].[K+].[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:40][CH3:41])=[C:34]([S:36](Cl)(=[O:38])=[O:37])[CH:35]=1)#[N:29]>O1CCCC1>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:40][CH3:41])=[C:34]([S:36]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=2[NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:38])=[O:37])[CH:35]=1)#[N:29]
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Reactant: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.7 %

Procedure:
To a solution of 0.125 g of ethyl N-[2-(2-aminoethyl)-5-isopropylphenyl]oxalamate in tetrahydrofuran (4 mL)-water (2 mL) were added successively 0.149 g of potassium carbonate and 0.125 g 5-cyano-2-methoxybenzenesulfonyl chloride, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.21 g of ethyl N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]oxalamate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C@@H:26]1([NH2:32])[CH2:30][CH2:29][CH2:28][C@H:27]1[NH2:31]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][C@@H:27]3[CH2:28][CH2:29][CH2:30][C@H:26]3[NH2:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: N[C@@H]1CCC[C@H]1N
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CCC[C@H]3N)c2c1

Procedure:
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and trans-cyclopentane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (d, J=7.83 Hz, 1 H), 7.93-7.81 (m, 2 H), 7.67 (t, J=7.45 Hz, 1 H), 7.61 (d, J=8.59 Hz, 1 H), 7.51 (t, J=7.71 Hz, 1 H), 7.47 (d, J=7.58 Hz, 1 H), 6.04 (s, 1 H), 5.25 (s, 2 H), 4.66 (brs, 1 H), 4.40 (brs, 1 H), 4.27 (d, J=7.07 Hz, 1 H), 3.84 (q, J=7.66 Hz, 1 H), 3.75-3.65 (m, 2 H), 2.45 (s, 3 H), 2.40-2.24 (m, 2 H), 2.08-1.79 (m, 3 H), 1.58 (dd, J=13.01, 7.71 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a suspension of 2-bromo-4-(trifluoromethoxy)phenol (3 g, 11.7 mmol) and potassium carbonate (3.23 g, 23.4 mmol) in N,N-dimethylformamide (35 mL) was added benzyl bromide (2.1 mL, 17.5 mmol) dropwise and stirred at room temperature for 16 hours. Reaction mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography eluting with ethyl acetate:hexane (2:98, by volume) afforded the title compound, 3.3 g, 81% yield.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26]/[C:27](=[N:58]\[OH:59])/[C@H:28]([NH:35][C:36]([CH:38]1[N:42]([S:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)(=[O:45])=[O:44])[CH2:41][CH2:40][S:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:49]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:50]=[CH:51][C:46]([S:43]([N:42]2[CH2:41][CH2:40][S:39][CH:38]2[C:36]([NH:35][CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:27](/[NH:26][C:8](=[O:10])[CH2:7][CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:58]\[OH:59])=[O:37])(=[O:45])=[O:44])=[CH:47][CH:48]=1
Reactant: CC(C)(C)OCCC(=O)O
Reactant: N/C(=N\O)[C@H](NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OCCC(=O)N/C(=N/O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Carboxylic acid, e.g., 3-tert-butoxypropionic acid (35 mg, 0.24 mmol), was dissolved in THF (2 mL). The resulting solution was cooled down to −15° C. NMM (84 μL, 0.76 mmol), followed by isobutyl chloroformate (33 μL, 0.25 mmol), were added. The mixture was stirred at −15° C. for 30 min. Intermediate Id, e.g. N-[(1R,2Z)-2-amino-2-(hydroxyimino)-1-phenylethyl]-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (108 mg, 0.22 mmol) in THF (2 mL) was added dropwise. The mixture was stirred overnight, letting the temperature increasing up to RT. Solvents were evaporated. The resulting oil was dissolved in AcOEt, and washed with sat NH4Cl and sat NaHCO3. Aqueous phases were extracted with two portions of AcOEt. Combined organic phases were dried over MgSO4, filtrated and evaporated, affording intermediate Id′, e.g. 3-(biphenyl-4-ylsulfonyl)-N-[(2E)-2-[(3-tert-butoxypropanoyl)amino]-2-(hydroxyimino)-1-phenylethyl]-1,3-thiazolidine-2-carboxamide (118 mg, 86% yield), which was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[NH:20][S:21]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:13]([CH:37]([CH3:39])[CH3:38])[CH:12]=1)[N:7]([CH3:40])[CH2:6][CH2:5]2.[ClH:41].O1CCOCC1>C(Cl)Cl>[ClH:41].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[NH:20][S:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:13]([CH:37]([CH3:38])[CH3:39])[CH:12]=1)[N:7]([CH3:40])[CH2:6][CH2:5]2
Reactant: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(NS(=O)(=O)C3CCN(C(=O)OC(C)(C)C)CC3)ccnc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(NS(=O)(=O)C3CCNCC3)ccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 4-(N-(3-(5-fluoro-1-methylindolin-6-yl)-1-isopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfamoyl)piperidine-1-carboxylate (D38) (442 mg, 0.773 mmol) in DCM (5 mL) at RT was added 4M HCl in 1,4-dioxane (1.933 mL, 7.73 mmol). The reaction mixture stirred at RT overnight. The reaction mixture was concentrated in vacuo to afford the title compound (500 mg). The material was used in next step without further purification. LCMS (A): m/z [(M−HCl)+H]+ 472, C24H30FN5O2S.HCl requires 507 (acidic).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>CC(C)=O>[CH2:23]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:24]
Reactant: CCI
Reactant: Cc1nnnn1-c1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccccc1-n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Acetone (3.2 L) and 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (228 g) were combined then stirred at ambient temperature for 15 minutes. Potassium carbonate (228 g) was added to the reaction mixture in a single portion. Iodoethane (366.8 g) was added dropwise to the reaction mixture producing a slight exotherm. The reaction mixture was heated at reflux for about 4 hours then stirred overnight while cooling to ambient temperature. The precipitated salts were removed by filtration then rinsed with acetone. The combined filtrates were evaporated under vacuum. The residue was dissolved in dichloromethane (1.5 L). The dichloromethane solution was washed with water (1.5 L), dried over magnesium sulfate then concentrated under vacuum to provide 227 g of ethyl-2-(5-methyl-1H-tetrazol-1-yl)benzoate as a white solid m.p. 98-100° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[CH:3]=1.[I:31]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[C:5]2[N:27]=[CH:28][N:29]([CH3:30])[C:4]=2[C:3]=1[I:31]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)cc3c2ncn3C)c(OC)c1
Solvent: CC#N
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)c(I)c3c2ncn3C)c(OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
In a round bottom flask, tert-butyl 6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1D, 7.887 g, 19.08 mmol) was dissolved in MeCN (200 mL) and cooled to 0° C. N-Iodosuccinimide (4.51 g, 20.03 mmol) was dissolved in the remaining MeCN (50 mL) and added dropwise to the reaction mixture over 40 min. The reaction mixture was stirred at 0° C. for an additional 10 min and was quenched with 2 M sodium hydrogensulfite (125 mL). Stirring and temperature were maintained for 50 min. The mixture was transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography using an Isco 120 g column eluting with 20-100% ethyl acetate/CH2Cl2 to provide tert-butyl 6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (8.436 g, 82% yield) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.CC#N>[CH2:31]([NH:38][C:39]([NH:30][C:29]1[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[N:13][C:12]=2[N:28]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: O=C=NCc1ccccc1
Solvent: CC#N
Solvent: CO
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)NCc4ccccc4)nc3n2)CC1
Yield: 63.4 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.08 g) from Example 36 was reacted with 0.298 g of benzyl isocyanate according to the general procedure of Example 37 to give 0.822 g of 1-benzyl-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=579; mp 144-148.5° C.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:12][N:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4]1.[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[CH:15]=1.[Cl-].[NH4+]>C(Br)C.O1CCCC1>[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:3]3[CH2:12][N:11]4[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]4)[CH2:5][CH2:4]3)([OH:28])[C:16]=2[CH:15]=1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Reactant: ClC1CCC2CCCCN2C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: C1CCOC1
Product: OC1(C2CCC3CCCCN3C2)c2ccccc2Sc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
Several drops of ethyl bromide were added to a stirred suspension of 1.29 g. (0.054 g.-atom) of magnesium turnings in 5 ml. of tetrahydrofuran under a nitrogen atmosphere. After the reaction began 9.3 g. (0.054 mole) of 3-chloroquinolizidine in 100 ml. of tetrahydrofuran was added. After the addition was completed the mixture was stirred and refluxed for one hour and cooled to 0° C. To the chilled suspension of the Grignard reagent was added a solution of 12.55 g. (0.051 mole) of 2-chloro-9-thioxanthone in 300 ml. of tetrahydrofuran. The solution was stirred at 24° C. for two hours, poured into aqueous ammonium chloride and extracted with ether. The extracts were washed with water, dried and evaporated to give 2-chloro-9-(3-quinolizidinyl)-9-hydroxythioxanthene.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[F:18].CI.[CH3:21]CC([O-])(C)C.[K+]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:21])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[F:18]
Reactant: CCC(C)(C)[O-]
Reactant: O=C1c2cc(Br)c(F)cc2CC12CCC(O)CC2
Agent: [K+]
Solvent: CI
Product: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=O
Temperature: 35 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of 6′-bromo-5′-fluoro-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 7, 1.94 g, 6.19 mmol) and methyl iodide (9.65 ml, 154 mmol) in 2-Me THF (80 mL) was heated to 35° C. Potassium tert-pentoxide (1.7 M in toluene) (5.01 g, 9.91 mmol) was slowly added dropwise over 10 min and the resulting mixture was stirred at 35° C. for 1 h. The reaction mixture was cooled to r.t., and partitioned between water and EtOAC. The organic phase was dried over magnesium sulfate and concentrated, to give the title compound (2.0 g, 99% yield). The product was used in the next step. MS (EI) m/z 326, 328 M+.