Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH2:14][CH2:15]1
Reactant: CN1CCC(O)CC1
Reactant: CC(=O)Nc1cccc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(OC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of N-(3-Hydroxy-phenyl)-acetamide (30.2 g) in anhydrous tetrahydrofuran (600 mL) was treated with 4-hydroxy-N-methylpiperidine (30.54 mL) and triphenylphosphine (68.18 g); a solution of diethylazadicarboxylate in anhydrous tetrahydrofuran (THF) (40.94 mL in 60 mL of THF) was added dropwise and the mixture was stirred at room temperature for 2 hours and then heated to 50° C. overnight. Further amounts of triphenylphosphine (28.00 g) and diethylazadicarboxylate (14 mL) were added and the heating was continued for additional 24 hours.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:9]=1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]1[CH2:18][CH2:17][C:16](=[CH2:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O[Li].O>C1COCC1.CO.O>[CH:20]([N:10]([C:11]([CH:13]1[CH2:14][CH2:15][C:16](=[CH2:19])[CH2:17][CH2:18]1)=[O:12])[C:9]1[CH:8]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:22])[CH3:21]
Reactant: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)OC)C(C)C)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.126 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then 1N aqueous solution of LiOH.H2O (0.8 mL, 0.800 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using chloroform and methanol (8:2) to obtain 3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (compound 28) (25 mg, 52%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ7.61 (d, J=7 Hz, 2H), 7.40-7.38 (m, 3H), 7.04 (s, 1H), 4.92 (m, 1H), 4.50 (d, J=7.6 Hz, 2H), 2.21-1.43 (m, 9H), 1.15 (bd, 3H), 0.93 (bd, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2>>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[N:1]1[C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]=2[C:10]1=[O:15]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(O)cc1F
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(O)cc1F

Procedure:
The filtrate from Step A was mixed with 9.74 g (0.0640 mole) of 3,4,5,6-tetrahydrophthalic anhydride, and the mixture was heated at reflux for approximately 64 hours. At the end of this period, the dark brown solution was poured over ice and extracted in succession with ethyl acetate and diethyl ether. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvents were evaporated under reduced pressure from the filtrate, leaving a dark brown oil as residue. This was placed on a silica gel column and eluted with methylene chloride/ethyl acetate (95/5). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 14.71 g of N-(2-fluoro-4-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide was recovered as an orange solid, m.p. 132°-136° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:13]([OH:15])=[N:12][CH:11]=[N:10][C:9]=2[O:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:5])C.[OH-].[Na+:26]>>[OH:15][C:13]1[C:14]2[C:6]([C:4]([O-:5])=[O:3])=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[O:8][C:9]=2[N:10]=[CH:11][N:12]=1.[Na+:26]
Reactant: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)oc2ncnc(O)c12
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])c1c(-c2ccc([N+](=O)[O-])cc2)oc2ncnc(O)c12

Procedure:
3.0 g (9.1 mmols) of 4-hydroxy-6-(4-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester are boiled for 50 min in ca. 50 ml of 5% sodium hydroxide solution. The reaction mixture is suction-filtered whilst hot and the residue discarded. [In order to obtain the sodium 4-hydroxy-6-(4-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylate, the cold filtrate (after cooling, needles form) is filtered by suction over ice and washed with a little ice water. The needles are dried in a HV. M.p. >250° C. (decomposition).] After cooling, the filtrate is carefully adjusted to pH 1 with conc. hydrochloric acid (a precipitate forms). Filtering by suction and drying of the residue in a HV yield the title compound as a solid, which melts at 300-302° C. (decomposition at the melting point):
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:5][N:4]=[C:3]1SC.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:5][N:4]=[C:3]1[N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CSc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)n1C
Product: Cc1nc(-c2cnc(N3CCCC3)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of Example C3 (0.087 g, 0.207 mmol) in pyrrolidine (1.75 mL, 21.31 mmol) was heated at 100° C. in a sealed vessel overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM). The material was treated with MeCN, sonicated and the resulting solid collected via filtration and dried to afford 3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidin-4(3H)-one (62 mg, 67%). 1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.58 (m, 4H), 3.45 (s, 3H), 2.35 (s, 3H), 1.87 (m, 4H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:21][N+:22]([O-:24])=[O:23])[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.C1COCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][CH:9]1[CH2:8][CH2:7][C:6]([CH2:5][C:4]([OH:25])=[O:3])([CH2:21][N+:22]([O-:24])=[O:23])[CH2:11][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])CCC(CNC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCC(CC(=O)O)(C[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 109.9 %

Procedure:
To a solution of [4-(tert-Butoxycarbonylamino-methyl)-1-nitromethyl-cyclohexyl]-acetic acid ethyl ester (0.304 g, 0.848 mmol) in MeOH (5.0 mL) and THF (1.5 mL) was added sodium hydroxide (4.2 mL, 1N, 4.2 mmol) and the reaction stirred at RT for 5 hr. The reaction was acidified to pH ˜2 with 1N HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide 0.308 g of crude product that was carried to the next step without purification. ESI-MS m/z 331 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:15])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13]O)C.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:4](=[O:3])[O:15][CH2:13][C:7]=2[CH:8]=1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Cl)cc2CO1
Temperature: 25 °C

Procedure:
To a solution of (4-chloro-2-hydroxymethyl-phenyl)-carbamic acid ethyl ester (71) obtained from the previous step in 5 mL of toluene was added 3 mL of DBU (2 equiv) and the resultant solution was heated at 110° C. overnight. After cooling to rt, the mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and dried in vacuo to give 6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one (72).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].C([O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:1]([O:3][C:4]1[CH:10]=[C:9]2[C:7](=[CH:6][CH:5]=1)[N:8]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]2[OH:13])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccc(N)cc1
Product: CCOC(=O)c1cnc2ccc(OCC)cc2c1O

Procedure:
Prepared as in Example 1c from 4-ethoxyaniline and diethyl 2-(ethoxymethylene)malonate as a white solid (26%). 1H NMR (400 MHz, DMSO-d6) δ 1.24-1.37 (m, 6H), 4.09 (q, J=6.8 Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 7.29-7.32 (m, 1H), 7.52-7.56 (m, 2H), 8.47 (s, 1H), 12.27 (s, 1H). MS 262 (MH+).
Reaction SMILES: C(OCC)(=O)C.Cl(O)(=O)(=O)=O.Cl([O-])(=O)(=O)=O.[CH3:17][CH:18]1[CH2:27][C:26]2[CH:25]=[C:24]3[O:28][CH2:29][O:30][C:23]3=[CH:22][C:21]=2[CH:20]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)[OH+:19]1.[NH:40]([C:42]1[N:47]=[CH:46][CH:45]=[CH:44][N:43]=1)[NH2:41]>C(O)(C)C>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([C:20](=[N:41][NH:40][C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[C:21]2[C:26]([CH2:27][CH:18]([OH:19])[CH3:17])=[CH:25][C:24]3[O:28][CH2:29][O:30][C:23]=3[CH:22]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: NNc1ncccn1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)[OH+]1)OCO3
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(O)Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2
Yield: 64 %

Procedure:
A stirred mixture of 3.29 g (9.99 mmol) of (±)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochroman-5-ol, 40 ml of ethyl acetate and 1.0 ml (1.15 mmol) perchloric acid was refluxed for 1 h. After cooling the precipitated (±)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-[1,3]dioxolo[4,5-g]isochromen-6-ylium perchlorate was filtered off, and it was stirred at reflux temperature with 1.6 g (14.55 mmol) of 2-hydrazinopyrimdine in 50 ml of isopropanol for 2 h, then concentrated. The residue was dissolved in dichloromethane and washed several times with water. After drying and evaporation the crude product was purified by column chromatography using silica gel (MN Kieselgel 60) as adsorbent and a mixture of toluene-ethyl acetate (0.1:4) as eluent to yield 2.71 g (64%) of the title compound; Mp.: 125-127° C.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[N:26]1([CH2:25][CH2:24][CH2:23][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[C:12]4[C:7]([N:6]=[C:5]5[C:14]=3[CH2:1][CH2:2][CH2:3][CH2:4]5)=[CH:8][CH:9]=[CH:10][CH:11]=4)=[CH:16][CH:17]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: ClCCCN1CCCC1
Reactant: Oc1ccc(-c2c3c(nc4ccccc24)CCCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc2c(-c3ccc(OCCCN4CCCC4)cc3)c3c(nc2c1)CCCC3
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The product from the previous step, 4-(1,2,3,4-Tetrahydro-acridin-9-yl)-phenol (22 mg, 0.08 mmol), 1-(3-Chloropropyl)-pyrrolidine (18 mg, 0.12 mmol), and K2CO3 (17 mg, 0.12 mmol) were mixed in NMP (267 uL) and stirred rapidly at 80° C. for 90 minutes in a sealed vial. The reaction mixture was cooled, partitioned between Et2O (50 mL) and H2O (10 mL). The organic layer was washed with H2O (3×10 mL), sat. aq. NaCl (10 mL), dried over Na2SO4, decanted and concentrated. The residue was purified using preparative LCMS to give product the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[CH2:18][CH2:17]3)[C:7]=2[CH:8]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: N#Cc1ccccc1N1CCN(Cc2csc3ccc(Cl)cc23)CC1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 2-(1-piperazinyl)benzonitrile were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.2-3.65 (m, 10H), 7.21 (m, 1H), 7.28 (d, 1H, J=7.8 Hz), 7.51 (dd, 1H, J=7.8, 1.5 Hz), 7.66 (m, 1H), 7.79 (dd, 1H, J=7.5, 1.5 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.25 (s, 1H), 8.40 (s, 1H). MS (DCI/NH3) m/z 368.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]3[CH2:16][CH2:15]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:32]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOCC>[ClH:32].[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]4[CH2:15][CH2:16]4)[C:4]=23)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CC4CC4)c23)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CC4CC4)c23)C1
Yield: 42 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(2-cyclopropylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (80 mg, 0.16 mmol) in neat TFA (3 mL) was stirred at room temperature for 30 minutes. TFA was then removed in vacuo. The oily residue obtained was dissolved in few drops of CH2Cl2 and treated with 2M HCl in ether (2 mL). The solid formed was filtered, washed with additional CH2Cl2 (3×3 mL). This material was dissolved in MeOH (0.5 mL), and CH3CN was added until the mixture became cloudy. The mixture was allowed to stand at room temperature. The solid formed was filtered, washed with additional CH3CN (2×2 mL), was dried under a stream of nitrogen first and then under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide hydrochloride (32 mg, 42% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.81 (s, 1H), 9.25 (s, 1H), 8.23 (s, 1H), 8.22 (br s, 3H), 7.54 (s, 1H), 3.45-3.38 (m, 2H), 3.36-3.26 (m, 2H), 3.10-3.04 (m, 1H), 2.31 (d, 2H), 2.15-2.08 (m, 1H), 1.86-1.79 (m, 1H), 1.72-1.62 (m, 1H), 1.53-1.45 (m, 1H), 1.13-1.06 (m, 1H), 0.54-0.51 (m, 2H), 0.24-0.21 (m, 2H); LCMS (APCI+) m/z 392.1, 394 (M+H)+, Retention time=2.23 minutes (Method 2).
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:26])([CH2:24][CH3:25])[C:21](Cl)=[O:22]>>[CH3:19][C:20]([CH3:26])([CH2:24][CH3:25])[C:21]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:21](=[O:22])[C:20]([CH3:26])([CH3:19])[CH2:24][CH3:25])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]1)=[O:22]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: C1COCCOCCNCCOCCOCCN1
Product: CCC(C)(C)C(=O)N1CCOCCOCCN(C(=O)C(C)(C)CC)CCOCCOCC1

Procedure:
Analogously to Example 2 from 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[CH:88]1([NH2:93])[CH2:92][CH2:91][CH2:90][CH2:89]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:88]1([NH:93][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[C:9]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:4]3[CH:3]=2)[CH2:92][CH2:91][CH2:90][CH2:89]1
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: NC1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.1 g, 0.25 mmol) in cyclopentylamine (5 mL) was added racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (46 mg, 0.08 mmol), cesium carbonate (120 mg, 0.38 mmol) and palladium (II) acetate (11 mg, 0.05 mmol). The resulting mixture was stirred at 80° C. for 24 hours, at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ethyl acetate and water were added to the reaction mixture. The phases were separated, and the aquous phase again extracted with ethyl acetate. The combined organics were dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (1:1 hexanes-ethyl acetate) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-amine (78 mg, 70%) as a white solid. 1H-NMR (CDCl3): δ 8.16 (d, 1H), 7.95 (d, 1H), 7.58 (q, 2H), 7.38 (d, 1H), 7.12 (t, 2H), 6.24 (dd, 1H), 6.20 (d, 1H), 5.05 (d, 1H), 4.40 (m, 1H), 4.13 (m, 1H), 3.89 (m, 1H), 1.5–2.2 (m, 16H);19F-NMR (CDCl3): δ −113.7; MS m/z 457 (M+1).
Reaction SMILES: [Si]([CH2:17][CH2:18][NH2:19])(OCCOC)(OCCOC)OCCOC.[Si:20]([CH2:30][CH2:31][CH2:32][NH2:33])([O:27][CH2:28]C)([O:24][CH2:25]C)[O:21][CH2:22]C.[Si](CCCN)(OCCOC)(OCCOC)OCCOC.[Si](CCCOCCCN)(OCC)(OCC)OCC.[Si](COCCN)(OCC)(OCC)OCC>>[Si:20]([CH2:30][CH2:31][CH2:32][NH:33][CH2:17][CH2:18][NH2:19])([O:27][CH3:28])([O:24][CH3:25])[O:21][CH3:22]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: COCCO[Si](CCN)(OCCOC)OCCOC
Agent: CCO[Si](CCCOCCCN)(OCC)OCC
Agent: CCO[Si](COCCN)(OCC)OCC
Agent: COCCO[Si](CCCN)(OCCOC)OCCOC
Product: CO[Si](CCCNCCN)(OC)OC

Procedure:
(CH3OCH2CH2O)3Si(CH2)2NH2 ; (C2H5O)3Si(CH2)3NH2 ; (CH3OCH2CH2O)3Si(CH2)3NH2 ; (C2H5O)3Si(CH2)3O(CH2)3NH2 ; (C2H5O)2C6H5Si(CH2)3O(CH2)3NH2 ; (C2H5O)3SiCH2O(CH2)2NH2 ; C2H5)Si(CH)0 (CH)NH(C2H5O)2CH3Si(CH2)3NH2 .
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>C(#N)C>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:33](=[O:34])[CH2:32][Cl:31])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)CCl
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CNC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 210 mg (0.53 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 10 ml of acetonitrile is added 49 μl (0.61 mmol) of chloro-acetyl chloride (Fluka, Buchs, Switzerland) and 85 μl (0.61 mmol) of triethylamine. The solution is stirred for 5 h at RT. trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-chloro-acetamide is obtained after purification of the crude mixture by medium-pressure liquid chromatography. Analytical HPLC: tR=6.94 min (Grad 2); ES-MS: m/eo=476.0.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.[OH:19][S:20]([OH:23])(=[O:22])=[O:21].[C:24](I)([F:27])([F:26])[F:25].OO>CS(C)=O>[S:20]([OH:23])([OH:22])(=[O:21])=[O:19].[F:25][C:24]([F:27])([F:26])[C:1]1[N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:4]2=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: FC(F)(F)I
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (5.20 g, 21.6 mmol) in DMSO (104 mL) was added H2SO4 (1.27 mL, 23.8 mmol) (note: exothermic), ferrous sulfate heptahydrate (6.5 mL of 1.0 M, 6.5 mmol) followed by CF3I (4.24 g, 21.6 mmol) by slow bubbling through the solution and taking weight difference of cannister. The mixture cooled with a ice-water bath before H2O2 (2.45 mL of 30% w/v, 21.6 mmol) was added drop-wise over 10 min keeping temperature <23° C. The mixture was allowed to stir for 15 min before it was poured onto ice (250 g) producing a white precipitate. The slurry was stirred for 5 min and then the solid was collected via filtration. The off-white solid was taken up in acetonitrile (150 mL) and was heated at reflux of 1 h. The solvent was removed and the solid was recrystallized from EtOH (15 mL/g) and water (5 mL/g). The solid was collected and dried to give 1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] sulfate (2.9 g, 33%). ESI-MS m/z calc. 308.1, found 309.1 (M+1)+; Retention time: 1.23 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=1[F:26]>>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])=[CH:19][C:18]=1[F:26]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)c1ccc(Br)c(F)c1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Br)c(F)c1

Procedure:
1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17, 1.25 g, 6 mmol) was reacted with 4-bromo-3-fluorobenzoic acid (1.1 g, 5.0 mmol) in an analogous manner to that described in Method 16 to give the title compound, which was used without further purification; Mass Spectrum: (M+H+-Boc) 311.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:27]C)=[CH:25][CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(N)=CC=1)(C)(C)C.Cl.O1CCOCC1.C1C2C(=CC=CC=2)C=NN=1>CO.CCOC(C)=O.O.N>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cn1
Agent: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2nnc(Cc3ccc(O)nc3)c3ccccc23)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
1-(4-tert-Butyl-anilino)-4-[6-methoxy-(pyridin-3-yl)-methyl]-phthalazine: Under N2 atmosphere, 0.40 g (2.7 mMol) of 4-tert-butyl-aniline and 0.62 ml 4 N HCl/dioxane are added to 750 mg (2.6 mMol) of 1-chloro-4-[6-methoxy-pyridin-3-yl)-methyl]-phthalazine in 11 ml of methanol, and the mixture is stirred for 2 h at 65° C. After cooling, the resulting yellow solution is diluted with EtOAc, 20 ml of water and 10 ml of 2.5% NH3 solution, and the aqueous phase is removed and extracted twice with EtOAc. The organic phases are washed with water and brine, dried and partially evaporated with a RE. After addition of DIPE to the remnant, the ftile compound crystallizes out: FAB-MS: (M+H)+=399; HPLC(Grad20-100) tRet=11.9.