Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:21][CH3:22])[O:13][CH2:12]2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.I[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:30]([N:10]([CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:21][CH3:22])[O:13][CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]2[C:1]1=[O:28])[CH2:31][CH3:32]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCCCN1C(=O)c2ccccc2C1=O)C1COc2cccc(OC)c2C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
1.5 mmol of the compound prepared in Example 1 is dissolved in 10 ml of dimethylformamide in the presence of 4.4 mmol of 1-iodopropane and 4.4 mmol of potassium carbonate. After 24 hours, stirring at 60° C., the solvent is evaporated off and the crude reaction mixture is taken up with 10 ml of water and extracted with dichloromethane. The organic phase is dried and evaporated and the expected product is obtained after purification by chromatography on a silica column (elution solvent: ether/petroleun ether, 1:99).
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.CCN1C2C(=CC3N=C4C(=C(Cl)C5C(=C4Cl)OC4C=C6N(CC)C7C(=CC=CC=7)C6=CC=4N=5)OC=3C=2)C2C1=CC=CC=2>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: CCn1c2ccccc2c2cc3c(cc21)Oc1c(Cl)c2c(c(Cl)c1=N3)Oc1cc3c(cc1N=2)c1ccccc1n3CC
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
To 240 g of polyphosphoric acid (116% phosphoric acid) heated at 85° C. was added 0.15 g of Carbazole Violet followed by 60 g of 2,5-dianilinoterephthalic acid. The mixture was heated at 120°-125° C. for two hours. After the melt was cooled to 95° C., the acid strength was adjusted to 110% by the dropwise addition of phosphoric acid. The resultant melt was stirred for 15 minutes and then slowly poured into 400 g of methanol at 24° C. During the drown, the temperature was allowed to increase to 60° C., with the temperature being controlled by external cooling and adjustment of melt addition rate. The slurry was heated at reflux (68°-72° C.) for one hour, diluted with water, and stirred at 60° C. for 30 minutes. The solid component was collected by filtration and washed with water until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to greater than 7, 5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90° C. for two hours. The slurry was cooled, filtered, and washed with water until alkali free, then reslurried in water. After adjustment of the pH to greater than 9.0-9.5, 3.2 g of a cycloaliphatic carboxylic acid was added. The resultant slurry was heated at about 140°-145° C. for four hours in a closed system, cooled to less than 45° C., acidified with phosphoric acid, and stirred. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 50 g of quinacridone as a violet pigment.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[OH-].[Na+]>ClCCCl>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Glacial acetic acid (1.3 mL, 22.7 mmol) and sodium triacetoxyborohydride (6.73 g, 31.7 mmol) were added to a solution of 5-aminoindole (3 g, 22.7 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.52 g, 22.7 mmol) in 1,2-dichloroethane (100 mL). The reaction mixture was stirred for 4 hours at room temperature; an aqueous solution of NaOH (1 M, 100 mL) was then added. The organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure to give 6.9 g (96% yield) of 4-(1H-indol-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a black foam; this material was used without further purifications for the next step.
Reaction SMILES: C12(C)C(C)(C)C(CC1)CC2C(Cl)=O.N[CH:15]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]1=[O:17].CC[N:25](CC)CC>C(Cl)(Cl)Cl>[NH2:25][N:18]1[C:19](=[O:22])[CH2:20][CH2:21][CH2:15][C:16]1=[O:17]
Reactant: CCN(CC)CC
Reactant: NC1CCC(=O)NC1=O
Agent: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Solvent: ClC(Cl)Cl
Product: NN1C(=O)CCCC1=O
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of (+)-camphanic chloride (19 mg, 00868 mmol), aminoglutarimide (21 mg, 0.0868 mmol) and Et3N (24 μl) in CHCl3 (1 ml) was stirred at room for 16 hours. The solution was diluted with CHCl3, washed with saturated aqueous solution of NaHCO3, dried over Na2SO4, concentrated and purified by chromatography (silica gel, CH2Cl2; EtOAc=10:1) to give product (16 mg, 60.0% yield) as a colorless gel: 13CNMR (CDCl3) δ 172.6, 169.4, 168.6; 165.5, 90.3, 58.3, 53.3, 48.2, 47.6, 29.2, 28.2, 26.9, 22.7, 14.6, 7.6; MS (CI/CH4) m/z 308 (M+). This compound exhibited angiogenic activity in the assay of Example 13.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C@@H:14]([OH:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:15][C@H:14]([O:16][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccccn1
Reactant: C[C@H](O)COc1ccc(Oc2ccccc2)cc1
Product: C[C@@H](COc1ccc(Oc2ccccc2)cc1)Oc1ccccn1

Procedure:
The resulting (S)-(+)-1-(4-phenoxyphenoxy)-2-propanol was reacted with 2-chloropyridine in the same manner as described in Example 1 to give (S)-(+)-2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[C:14](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][PH:26](=[O:28])[CH3:27].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[C:14](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]([O:17][CH2:18][CH2:19][CH2:20][P:26]([CH3:27])([CH3:25])=[O:28])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[PH](C)=O
Reactant: C=CCOC(=O)c1ccccc1Nc1ccnc2cc(Cl)ccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CP(C)(=O)CCCOC(=O)c1ccccc1Nc1ccnc2cc(Cl)ccc12

Procedure:
A mixture of 3.37 grams (0.01 mol) of allyl 7-chloro-4-quinolyl-anthranilate (melting point 112° C.) dissolved in 60 ml of toluene and 1.17 grams (0.015 mol) of dimethylphosphine oxide is heated to 100° C. 30 mg of α,α'-azo-bis-isobutyronitrile in 10 ml of toluene are then added dropwise to catalyse the addition of the dimethylphosphine oxide to the allyl double bond. From the cooled solution, 3-(dimethylphosphinyl)-propyl N-(7-chloro-4-quinolyl)-anthranilate is isolated; melting point 162° C. (after recrystallisation from acetone); yield: 3.58 grams (86% of theory).
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[CH:47]=[N:48][O:49][CH:50]=1>>[O:49]1[CH:50]=[C:46]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][N:11]3[C:10]4[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]5[CH:43]=[CH:42][C:41]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:35]=5)=[CH:31][C:9]=4[N:8]=[C:7]3[CH2:6][C:2]([CH3:44])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:14][CH:15]=2)[CH:47]=[N:48]1
Reactant: Brc1cnoc1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(-c2cnoc2)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 4-bromoisoxazole. MS (ESI): mass calcd. for C32H28N4O4, 532.21; m/z found, 533.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.18 (d, J=7.8, 1H), 9.08 (s, 1H), 8.82 (s, 1H), 8.42 (d, J=8.6, 1H), 8.35 (d, J=8.2, 1H), 8.24-8.17 (m, 2H), 7.98 (t, J=7.4, 1H), 7.67-7.64 (m, 4H), 7.45 (d, J=8.0, 1H), 7.34 (d, J=7.0, 2H), 5.88 (s, 4H), 3.59 (s, 2H), 1.44 (s, 6H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:41]5[CH:42]=[CH:43][C:38]([CH2:37][NH:36][C:34](=[O:35])[O:33][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:39][CH:40]=5)[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)cc1

Procedure:
tert-Butyl 4-(3-(1-(2,2-difluorobenzo[d][,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzylcarbamate was made by the procedure shown above starting from N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide and 4-((tert-butoxycarbonylamino)methyl)phenylboronic acid. ESI-MS m/z calc. 573.2. found 574.3 (M+1)+. Retention time 2.26 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.40 (s, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.74-7.70 (m, 1H), 7.61 (d, J=1.2 Hz, 1H), 7.54-7.38 (m, 8H), 4.22 (d, J=5.9 Hz, 2H), 1.57-1.55 (m, 2H), 1.41 (s, 9H), 1.22-1.20 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17]([CH3:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2].[CH:20]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:27][CH2:26][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17]([CH3:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cc(S(C)=O)ccc3nc21
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(S(C)=O)ccc3nc21
Temperature: 110 °C
Yield: 11.1 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-(methylsulfinyl)-1H-pyrazolo[3,4-b]quinoline (0.4 g, 2.8 mmol), DMSO (1.5 ml) and cyclohexylmethylamine (0.73 ml, 5.6 mmol) is heated at 110° C. over night. The reaction mixture is cooled to room temperature, then is partitioned between CHCl3 (20 ml) and water (20 ml) containing NH4OH (3 ml). The layers are separated, the aqueous layer is extracted with CH2Cl2 (10 ml), and the organic layers are combined dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate, followed by recrystallization from ethyl acetate (2×) to afford 0.115 g of 1-ethyl-6-(methylsulfinyl)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 186°-187° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:33][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])(=[O:24])=[O:23])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccccc3OC)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1S(=O)(=O)N1CCC(c2c(C)c(CC(=O)O)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of {6-fluoro-4-[1-(2-methoxy-benzenesulfonyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (64 mg, 0.132 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (63.3 mg, 1.5 mmol) in water (2 mL). The reaction mixture was stirred at room temperature overnight under nitrogen. After this time, the reaction mixture was concentrated. Water (˜20 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (2.7 mL). The resulting white precipitate was collected by vacuum filtration, washed with hexanes, and then further dried under vacuum to provide {6-fluoro-4-[1-(2-methoxy-benzenesulfonyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid (51.5 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br. s, 1H), 8.04 (br. s, 1H), 7.85-7.92 (m, 1H), 7.78-7.84 (m, 1H), 7.67 (s, 2H), 7.29-7.37 (m, 2H), 7.13 (t, J=8.00 Hz, 1H), 3.94 (s, 3H), 3.82-3.92 (m, 2H), 3.70-3.80 (m, 2H), 2.82-3.02 (m, 2H), 2.35 (s, 3H), 2.13-2.32 (m, 1H), 1.60-1.71 (m, 2H). MS cald. for C25H27FNO5S [(M+H)+]: 472, obsd. 472.2.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:12])[CH:9]=2)[N:4]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[N:16]1[CH:17]=[CH:18][C:19]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][C@@H:14]4[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]4)=[O:12])[CH:9]=3)[N:4]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:3]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 190 %

Procedure:
A flask was charged with tert-butyl (3R)-3-{[(3-bromo-1-trityl-1H-indazol-5-yl)carbonyl]amino}piperidine-1-carboxylate (4.00 g, 6.01 mmoles), potassium phosphate (2.05 g, 9.66 mmoles) and 1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (160.0 mg, 0.219 mmoles). The flask was put under an atmosphere of argon (3× vacuum/argon cycle) and degassed dioxane (20 mL) and water (5 mL) were injected. The reaction was heated to 80° C. for 16 hours and was then allowed to cool to ambient temperature. The resulting solution was poured into water (100 mL) and the aqueous emulsion was washed three times with chloroform/isopropanol (4:1, 50 mL portions). The combined organic washings were dried over sodium sulfate, filtered and concentrated to dryness. Flash chromatography (gradient 0-15% dichloromethane/methanol) to yield tert-butyl (3R)-3-({[3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl]carbonyl}amino)piperidine-1-carboxylate as a white solid (3.79 g, 95%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:27]([O:29]C)=[O:28])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:14])(=O)C.[OH-].[Na+:32]>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][C:13]([NH:15][C@H:16]([C:27]([O-:29])=[O:28])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:14].[Na+:32]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccccc1O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 94 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 2 (5.0 g), 1 mol/L of an aqueous sodium hydroxide solution (37 mL), and methanol (300 mL), to give the captioned compound (4.3 g, 94%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:4][C:3]4[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=4[Cl:1])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Fc1ccc(CCl)c(Cl)c1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3ccc(F)cc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 2-chloro-4-fluorobenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (26% yield). 1H NMR (300 MHz, CDCl3) δ 7.92-8.03, 7.38-7.50, 7.06-7.14, 6.88-7.03, 3.68-3.78, 3.62, 3.46-3.58, 2.55-2.69, 1.42-1.54, 0.68-0.80, 0.40-0.49, 0.02-0.13. MS (ES+) m/z 418 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([N:39]([CH3:41])[CH3:40])=[O:38])=[CH:35][C:34]=1[CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:41][N:39]([CH3:40])[C:37](=[O:38])[C:36]1[CH:42]=[CH:43][C:33]([NH:32][C:2]2[N:3]=[C:4]([O:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=3[N:7]=2)=[C:34]([CH3:44])[CH:35]=1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cn1
Reactant: Cc1cc(C(=O)N(C)C)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N(C)C)ccc1Nc1nc(OC2CCOCC2)c2c(-c3cnn(C)c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a degassed mixture of 2-chloro-5-(1-methyl-1H-pyrazol-4-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 4-amino-N,N,3-trimethylbenzamide (1 equiv) and cesium carbonate (3 equiv) in 1.4-dioxane (0.086 M) were added palladium acetate (0.3 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.6 equiv). The mixture was stirred at 110° C. for 2 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated and the residue obtained was purified by preparative thin layer chromatography (3.3% MeOH in DCM) to afford the title compound (76% yield). MS (ESI) m/z 606.1 [M+1]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1.CS(C)=O>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Solvent: Clc1ccccc1
Product: O=C=NC1CCCCC1
Yield: 178.3 %

Procedure:
500 g of chlorobenzene and 2 g of dimethyl sulfoxide (0.025 mol) were placed in the glass vessel and 35 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 78° C., with vigorous phosgene reflux being established. While stirring vigorously at 78–82° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 113 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 78–82° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 40° C. by means of nitrogen. The reaction mixture obtained was a fluid suspension from which the solid obtained was separated by filtration. 2.2 g of solid were able to be isolated in this way. The filtered crude product was worked up by distillation. Removal of the solvent and fractional distillation gave 79.7 g of cyclohexyl isocyanate (0.631 mol). This corresponds to 63.1% of the theoretical yield.
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH2:19]([N:21]([CH2:28][CH3:29])[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)[CH3:20]>C1C=CC=CC=1>[CH:7]1[C:6]2[CH:5]([N:24]3[CH2:25][CH2:26][CH2:27][CH:22]([N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])[CH2:23]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CCN(CC)C1CCCNC1
Solvent: c1ccccc1
Product: CCN(CC)C1CCCN(C2c3ccccc3Oc3ccccc32)C1

Procedure:
A solution of 9.92 g. of 9-acetoxyxanthene and 7.2 g. of 3-diethylaminopiperidine in 200 ml. of benzene is refluxed for 18 hours. Working up by the procedure of Example 1 gives 1-(9-xanthenyl)-3-diethylaminopiperidine.
Reaction SMILES: CI.[CH2:3](OC1C=CC(CCl)=CC=1)C1C=CC=CC=1.[C:19]1([S:25]([CH:28]2[C:33](=[O:34])[NH:32][CH2:31][CH2:30][N:29]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25]([C:28]2([CH3:3])[C:33](=[O:34])[NH:32][CH2:31][CH2:30][N:29]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1S(=O)(=O)c1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1(C)S(=O)(=O)c1ccccc1

Procedure:
When in the procedure of Example 3a, methyl iodide is substituted for p-benzyloxybenzyl chloride, and 27c is substituted for 2, the title compound is obtained.