Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C:14]2[CH:13]=[C:12]([C:15]3(O)[C:28]4[CH:27]=[C:26]([Br:29])[CH:25]=[CH:24][C:23]=4[C:22]([C:31]4[CH:43]=[CH:42][C:41]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[C:34]([CH3:45])([CH3:44])[C:33]=5[CH:32]=4)(O)[C:21]4[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.[PH2](=O)[O-].[Na+].[I-].[K+].[PH2](=O)O>C(O)(=O)C.O>[CH3:1][C:2]1([CH3:47])[C:14]2[CH:13]=[C:12]([C:15]3[C:16]4[C:21]([C:22]([C:31]5[CH:43]=[CH:42][C:41]6[C:40]7[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=7)[C:34]([CH3:45])([CH3:44])[C:33]=6[CH:32]=5)=[C:23]5[C:28]=3[CH:27]=[C:26]([Br:29])[CH:25]=[CH:24]5)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC1(C)c2ccccc2-c2ccc(C3(O)c4ccccc4C(O)(c4ccc5c(c4)C(C)(C)c4ccccc4-5)c4cc(Br)ccc43)cc21
Agent: O=[PH2]O
Agent: O=[PH2][O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2ccc(-c3c4ccccc4c(-c4ccc5c(c4)C(C)(C)c4ccccc4-5)c4cc(Br)ccc34)cc21
Reaction time: 2 h
Yield: 47.4 %

Procedure:
A solution of 46 mmol of 9,10-bis(9,9-dimethylfluorene-2-yl)-2-bromo-9,10-dihydroanthracene-9,10-diol, 24 g (0.23 mol) of sodium phosphinate monohydrate, and 15 g (91 mmol) of potassium iodide in 100 mL of glacial acetic acid was stirred for 4 hours at 120° C. After the reaction, 60 mL of a 50% phosphinic acid was added to the reaction mixture, and then stirring was kept for additional 2 hours at 120° C. Water was added to the mixture, and the mixture was stirred for 1 hour. After the mixture was filtered, the resulting solid was washed with water and dissolved in toluene, and the toluene-solution was washed with a saturated sodium bicarbonate aqueous solution and brine. Magnesium sulfate was added to this organic layer to dry the organic layer. This mixture was subjected to suction filtration, and the filtrate was filtered through celite, Florisil, and then alumina. The filtrate was concentrated, and the resulting solid was dissolved in a mixed solvent of chloroform and methanol, which was followed by irradiating ultrasound to yield 14 g of the title compound as a light yellow solid. Total yield of the steps of (ii) and (iii) was 47%.
Reaction SMILES: [CH:1]([O:4][P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[OH:6])([CH3:3])[CH3:2].[Na].[C:12](#[N:15])[CH:13]=[CH2:14]>>[C:12]([CH2:13][CH2:14][P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:6])[O:4][CH:1]([CH3:3])[CH3:2])#[N:15]
Reactant: CC(C)OP(O)C(C)(C)C
Reactant: C=CC#N
Agent: [Na]
Product: CC(C)OP(=O)(CCC#N)C(C)(C)C

Procedure:
To 15.7 g of t-butylphosphonous acid-isopropylester in 6.3 ml of acrylonitrile are added 21 ml of sodium isopropylate (0.25 molar). After the exothermic reaction (the temperature rises to 100°) the suspension is filtered, the filtrate evaporated and the residue distillated to yield isopropyl 2-cyanoethyl(t-butyl)phosphinate as an oil, b.p. 121°/8 Pa, nD20 =1.4480.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18](Cl)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:21]2[CH2:25][C@H:24]([N:26]3[N:30]=[N:29][C:28]([CH2:31][CH3:32])=[N:27]3)[C@@H:23]([OH:33])[C@H:22]2[OH:34])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[C:96]([O:100][C:101](=[O:108])[NH:102][C@@H:103]1[CH2:107][CH2:106][NH:105][CH2:104]1)([CH3:99])([CH3:98])[CH3:97]>>[C:96]([O:100][C:101](=[O:108])[NH:102][C@@H:103]1[CH2:107][CH2:106][N:105]([C:18]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[C@@H:21]3[CH2:25][C@H:24]([N:26]4[N:30]=[N:29][C:28]([CH2:31][CH3:32])=[N:27]4)[C@@H:23]([OH:33])[C@H:22]3[OH:34])=[C:11]([NH:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[C:35]3[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=3)[N:19]=2)[CH2:104]1)([CH3:99])([CH3:97])[CH3:98]
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-2-chloro-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate BF1) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 46) by replacing trans-1,4-diaminocyclohexane with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH-].[Na+].[O:10]1[CH2:12][CH2:11]1>O>[NH2:1][CH:2]([CH2:3][S:4][CH2:12][CH2:11][OH:10])[C:5]([OH:7])=[O:6]
Reactant: N[C@@H](CS)C(=O)O
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(CSCCO)C(=O)O
Temperature: 10 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
36.3 g of L-cysteine was dissolved in 300 ml of water. 24 ml 1 mol/L of NaOH solution was added into above solution and cooled by ice-water bath in order to adjust pH value to 7. And then at 0° C. 30 mL of epoxy ethane was added dropwise to the above solution and then mixture was cooled to 10° C. After the mixture was stirred for 1.0 hour, it was warmed to room temperature and then stirred for 1.5 hours. The resultant mixture was extracted with ethyl ether three times (60 ml, 45 ml, 45 ml) to remove the residual epoxy ethane. Water layer was removed on a rot-vap to obtain a buff solid. The solid was recrystallized in 95% ethanol to obtain a white lamellar crystal (33.9 g). Yield 69.4%□mp 195-196° C. (Dec.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:25])=[O:15]
Reactant: O=C(O)CCCCCCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCCCCCCCCCBr

Procedure:
A solution of 30 mmols (8.4 g) of 12-bromododecanoic acid and 10 ml of toluene in 5 ml of thionyl chloride was stirred at 80° C. for 1 hour. Excess thionyl chloride and toluene were distilled out under reduced pressure to obtain 12-bromododecanoyl chloride(acid chloride 9d). A solution of 25 mmols (8.2 g) of hydroxy ester 9c obtained in the above (9-5) was stirred with 30 mmols (3.0 g) of triethylamine in 100 ml of THF. A solution of said acid chloride 9c in THF, was added dropwise thereto followed by stirring for 8 hours. The reaction mixture was extracted with ether, washed with dilute aqueous hydrochloric acid solution, dried, concentrated and then purified by column chromatography to obtain the desired bromo ester 9e (12.1 g, yield 82% [α]23D=+2 35 (chloroform)).
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[C:6]1([NH:12][C:13]2[C:22]([NH2:23])=[C:21]3[C:16](C=CC=N3)=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[C:6]1([N:12]2[C:13]3=[C:14]4[C:15](=[CH:16][CH:21]=[C:22]3[NH:23][S:1]2(=[O:3])=[O:2])[CH:8]=[CH:7][CH:6]=[N:12]4)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NS(N)(=O)=O
Reactant: Nc1c(Nc2ccccc2)ccc2cccnc12
Solvent: c1ccncc1
Product: O=S1(=O)Nc2ccc3cccnc3c2N1c1ccccc1
Temperature: 115 °C
Yield: 36 %

Procedure:
Sulfamide (34 mg, 0.35 mmol) was added to a solution of N*7*-phenyl-quinoline-7,8-diamine 576 (56 mg, 0.23 mmol) in pyridine (2 ml) and the mixture was heated in a microwave at 115° C. for 2 h. After cooling, the solvent was removed in vacuo. The residue was dissolved in EtOAc (50 ml) and the organic phase was washed with sat. NaHCO3 solution (30 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography DCM/MeOH/TEA (98:2:0.5-90:10:0.5 gradient) followed by preparative HPLC (acidic conditions 1) to give the title compound (12.3 mg, 17%).
Reaction SMILES: C(Cl)(C(Cl)=O)=O.[CH:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]1[N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1)([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.Cl>C(Cl)Cl.CN(C=O)C>[CH:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]1[N:17]1[CH2:18][CH:19]([C:23]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:25])[CH2:20][C:21]1=[O:22])([CH3:8])[CH3:9]
Reactant: CC1CCC(C(C)C)C(N2CC(C(=O)O)CC2=O)C1
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(C(C)C)C(N2CC(C(=O)N3CCCCC3)CC2=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
(COCl)2 (10 g, 79 mmol, 6.9 mL) and DMF (50 μL) were carefully added to 1-(2-isopropyl-5-methyl-cyclohexyl)-5-oxo-pyrrolidine-3-carboxylic acid (obtained as in EXAMPLE II, 10 g, 37.4 mmol) suspended in anhydrous CH2Cl2 (150 mL). The reaction mixture slowly turned into a homogeneous solution over about 3 hours, which was then concentrated in vacuo and dissolved in anhydrous CH2Cl2. The reaction mixture was subsequently added dropwise to a mixture of DIEA (9.7 g, 74.8 mmol) and piperidine (3.99 g, 56 mmol) at 0° C. with stirring. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was poured into HCl (1 N) and extracted with CH2Cl2. The organic phases were collected, washed with brine, dried, and evaporated. Column chromatography with dichloromethane:methanol (95:5) provided 1-(2-isopropyl-5-methyl-cyclohexyl)-4-(piperidine-1-carbonyl)-pyrrolidin-2-one (10.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH:22]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[O:20])[CH2:15][CH2:14]1)[CH2:7]2.O[CH2:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:50]([O:49][C:47]([N:44]1[CH2:45][CH2:46][CH:41]([CH2:40][N:35]2[C:34]([CH:22]([NH:21][C:19]([N:16]3[CH2:15][CH2:14][CH:13]([N:8]4[CH2:7][C:6]5[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=5)[NH:10][C:9]4=[O:12])[CH2:18][CH2:17]3)=[O:20])[CH2:23][C:24]3[CH:25]=[C:26]4[C:30](=[C:31]([CH3:33])[CH:32]=3)[NH:29][N:28]=[CH:27]4)=[N:38][N:37]=[N:36]2)[CH2:42][CH2:43]1)=[O:48])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnn[nH]2)cc2cn[nH]c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnnn2CC2CCN(C(=O)OC(C)(C)C)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3[4H]-yl)-N-(2{7-methyl-1H-indazol-5-yl}-1-{1H-tetrazol-5-yl}ethyl)piperidin-1-carboxamide (50 mg, 0.1 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (22 mg, 0.11 mmol) in dry tetrahydrofuran (3.0 mL) at 0° C. was added in one portion triphenylphosphine (27.5 mg, 0.11 mmol) followed by a dropwise addition of diethylazodicarboxylate (10 μL, 0.105 mmol). The resulting mixture was stirred briefly at 0° C. and then allowed to warm to room temperature. After 16 h, the solvent was removed and the residue purified by column chromatography to afford tert-butyl-4-({5-(1-[4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3 [4H]-yl)piperidine-1-carboxamido]-2-(7-methyl-1H-indazol-5-yl)ethyl)-1H-tetrazol-1-yl}methyl)piperidine-1-carboxylate. MS: tR=1.44 min, 716.17 (MH)+ and tert-butyl-4-({5-(1-[4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3[4H]-yl)piperidine-1-carboxamido]-2-(7-methyl-1H-indazol-5-yl)ethyl)-2H-tetrazol-1-yl}methyl)piperidine-1-carboxylate. MS: tR=1.45 min, 716.16 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)OCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 538.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[C:20]([F:39])[CH:19]=2)=[O:16])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:36][O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[O:37][CH3:38])[N:28]=[CH:27][CH:26]=[C:25]2[O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15]([C:4]2[C:5](=[O:14])[N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=[C:2]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:3]=2)=[O:16])=[CH:19][C:20]=1[F:39]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4cc(Br)cn(-c5ccccc5)c4=O)cc3F)c2cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cc(-c5ccccc5)cn(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 80 °C
Yield: 92.3 %

Procedure:
5-Bromo-N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-2-oxo-1-phenyl-1,2-dihydro-pyridine-3-carboxamide (0.075 g, 0.13 mmol) was suspended in DMF (1.5 mL) and then was added a solution of potassium carbonate (0.053 g, 0.38 mmol) in water (0.5 mL), phenylboronic acid (0.015 g, 0.13 mmol) and PdCl2(dppf)2 (0.0093 g, 0.013 mmol). The reaction mixture was heated at 80° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and water then extracted with ethyl acetate. The organic layer was washed with brine then dried over sodium sulfate and concentrated under vacuum. The remaining residue was purified by silica gel chromatography (1% methanol/dichloromethane to 2% methanol/dichloromethane) to give N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-2-oxo-1,5-diphenyl-1,2-dihydropyridine-3-carboxamide as a light yellow solid (0.069 g, 0.12 mmol, 92% yield). MS (ESI pos. ion) m/z: 588 (MH+). Calc'd exact mass for C35H26FN3O5: 587. 1H NMR (400 MHz, DMSO-d6) 12.19 (s, 1H), 8.87 (d, J=2.91 Hz, 1H), 8.40-8.55 (m, 2H), 8.09 (dd, J=12.82, 2.34 Hz, 1H), 7.75 (d, J=7.33 Hz, 2H), 7.16-7.67 (m, 12H), 6.49 (d, J=5.05 Hz, 1H), 3.95 (s, 6H).
Reaction SMILES: Cl[Si](C)(C)C.[NH2:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([CH2:17][C@@H:18]([O:34]CC2C=CC=CC=2)[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[CH:9][C:8]=1[Cl:42].[Na+].[I-].N>C(#N)C.C(O)(C)C.CCO>[NH2:6][C:7]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([CH2:17][C@@H:18]([OH:34])[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)[CH2:23][CH2:22]2)=[O:20])=[CH:9][C:8]=1[Cl:42]
Reactant: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OCc3ccccc3)CC2)CC1
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [I-]
Solvent: CCO
Solvent: CC#N
Solvent: CC(C)O
Product: CN1CCN(C2CCN(C(=O)[C@H](O)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
0.32 mL (2.5 mmol) chloro-trimethyl-silane were added to a suspension of 450 mg (0.84 mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-propan-1-one and 380 mg (2.5 mmol) NaI in 30 mL acetonitrile and the reaction mixture was stirred for 7 h at 80° C. 30 mL EtOH and 20 mL isopropanol were added, the mixture was stirred for 30 min at RT, 15 mL of NH3 solution were added and the mixture was stirred for a further 30 min. It was evaporated down i. vac., the residue was combined with 100 mL 15% K2CO3 solution, extracted with 100 mL EtOAc, the organic phase was separated off, washed with 3% Na2SO3 solution and trocknete over Na2SO4. After the desiccant and solvent had been eliminated the residue was further reacted without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:23]4([CH2:27][O:26][C:25]([N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:24]4)[C:19]4([CH2:22][O:21][CH2:20]4)[C:15]4([CH2:18][CH2:17][CH2:16]4)[O:14][C:11]3=[CH:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1.[C:43]([CH:45]1[CH2:47][CH2:46]1)#[CH:44]>CCN(CC)CC.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:45]1([C:43]#[C:44][C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:23]5([CH2:27][O:26][C:25]([NH2:28])=[N:24]5)[C:19]5([CH2:20][O:21][CH2:22]5)[C:15]5([CH2:16][CH2:17][CH2:18]5)[O:14][C:11]4=[CH:12][CH:13]=3)[CH:5]=[N:6][CH:7]=2)[CH2:47][CH2:46]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(-c3cncc(Br)c3)ccc1OC1(CCC1)C21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC1=NC2(CO1)c1cc(-c3cncc(C#CC4CC4)c3)ccc1OC1(CCC1)C21COC1
Reaction time: 1 h
Yield: 15.6 %

Procedure:
To a stirred solution of di-tert-butyl [6′-(5-bromopyridin-3-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl]imidodicarbonate (48 mg, 0.075 mmol) in Et3N (0.67 ml) were added ethynylcyclopropane (0.063 mL, 0.75 mmol), PdCl2(PPh3)2 (10 mg, 0.015 mmol) and CuI (5.7 mg, 0.030 mmol) at room temperature and the mixture was sealed and irradiated with microwave at 150° C. for 1 hour. To this mixture was added activated carbon (ca. 100 mg) and the mixture was stirred for 1 hour to remove palladium residues. The mixture was passed through a pad of Celite. The filtrate was evaporated to give a residue. To the solution of the residue in toluene (3 ml) was added silica gel (500 mg) and the mixture was refluxed for 2 hours. The mixture was passed through a pad of Celite and the filtrate was evaporated to give a crude product, which was purified with column chromatography (MeOH in CHCl3=0 to 10%) to give 6′-[5-(cyclopropylethynyl)pyridin-3-yl]trispiro[cyclobutane-1,2′ chromene-4′,4″-[1,3]oxazole-3′,3′″-o xetan]-2″-amine (5 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22].[Cl-].[NH4+]>C(OCC)(=O)C.C1COCC1>[C:12]1([CH2:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[CH:9][CH:8]=2)=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(C(=O)Cc2ccccc2)cc1)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
With cooling with ice, 60% oily sodium hydride (804 mg) was added to a THF (100 mL) solution of 1-(4-hydroxyphenyl)-2-phenylethanone (4.7 g, 22.1 mmol), and stirred for 10 minutes. With cooling with ice, chlorotriisopropylsilane (5.2 mL) was added to the reaction liquid, and stirred for 2 hours. Aqueous saturated ammonium chloride solution was added to the reaction liquid, then diluted with ethyl acetate and extracted. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1). The obtained crude product was recrystallized from ethanol to obtain the intended compound (3.8 g, 31%).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1)#[N:2]
Reactant: NCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1
Reactant: N#Cc1ccccc1OCC1CO1
Product: N#Cc1ccccc1OCC(O)CNCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:19]([O:21][C:22]([CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:28][CH2:27][N:26]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
4-Methoxy-benzoyl chloride (185 mL, 1.36 mol) and triethylamine (259 mL, 1.86 mol) were added to a stirred solution of pyrrolidine-3-carboxylic acid ethyl ester (177.5 g, 1.24 mol) (see Preparation 1) in THF (2500 mL) at 10° C. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 10% citric acid aqueous solution (2000 mL) then ethyl acetate (2000 mL) was added. The organic layer was washed with saturated aqueous NaHCO3 (2000 mL) and water (2000 mL), dried over magnesium sulphate then concentrated under reduced pressure to afford the title compound as a brown oil (285.3 g, 83%).
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH3:13][OH:14]>>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([O:14][CH3:13])=[CH:4][CH:5]=1
Reactant: CO
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Na]
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 130 °C
Yield: 41 %

Procedure:
Sodium (12.78 g; 555 mmol) was added to dry MeOH (100 ml). When the gas evolution ceased, the reaction mixture was evaporated to dryness and dry NMP (250 ml) followed by Cu (s) (35.3; 555 mmol) and 4-bromo-trifluoromethylbenzene (25 g; 111 mmol) was added. The reaction mixture was heated to 130° C. for 4 h, cooled to rt. and filtered. Water (500 ml) was added to the filtrate and it was extracted with Et2O (2×200 ml). The combined organic fractions were washed with H2O (2×100 ml), dried (MgSO4) and evaporated to dryness. Column chromatography gave 8.05 g (41%) of product.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[CH:7][N:6]=1)=[O:4]>[OH-].[Na+]>[CH3:9][C:11]([C:7]1[C:8]([OH:15])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1ncc(O)c(C(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1nc(C(=O)O)nc(C(C)(C)C)c1O
Yield: 143.3 %

Procedure:
A solution of 4,6-his (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxylic acid methyl ester (500 mg) in 1N NaOH (50 mL) is heated at reflux for 1 hour. The reaction mixture is cooled, filtered, and acidified to pH 4 with 1N HCl. The resulting precipitate is collected by filtration and dried at room temperature under vacuum to give pure 4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxylic acid (430 mg); mp 200° C. dec.