Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH:35]([CH3:37])[CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:38][O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][CH:50]([N:53]5[CH2:58][CH2:57][N:56]([S:59]([CH3:62])(=[O:61])=[O:60])[CH2:55][CH2:54]5)[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH:35]([CH3:37])[CH3:36]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Reactant: CC(C)Oc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC(C)C)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 35.2 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]benzamide (Intermediate Example 7) (0.10 g, 0.19 mmol), 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 58, Step B) (0.071 g, 0.19 mmol) and para-toluenesulfonic acid (0.088 g, 0.46 mmol) in i-PrOH (5 mL) was heated in a microwave at 175° C. for 25 min. The reaction mixture was concentrated onto silica gel and purified by flash chromatography. Recrystallization from DCM and diethyl ether afforded N-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]-5-(3-{2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzamide (0.057 g, 35%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (s, 1H), 9.36 (br. s., 1H), 8.45 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.08 (d, J=1.9 Hz, 1H), 7.66-7.80 (m, 2H), 7.35-7.49 (m, 3H), 7.31 (d, J=8.8 Hz, 1H), 7.15-7.26 (m, 2H), 6.96 (t, J=6.6 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.57 (d, J=5.1 Hz, 1H), 6.49 (dd, J=8.8, 2.3 Hz, 1H), 4.83-4.95 (m, 1H), 3.81 (s, 3H), 3.71-3.78 (m, 2H), 3.04-3.14 (m, 4H), 2.87 (s, 3H), 2.64-2.72 (m, 2H), 2.58-2.63 (m, 4H), 2.38-2.47 (m, 1H), 1.77-1.90 (m, 2H), 1.47-1.63 (m, 2H), 1.41 (d, J=6.0 Hz, 6H). MS (M−H, ES−) 850.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([C@@H:17]([CH2:21][CH2:22][C:23]([OH:25])=O)[C:18]([OH:20])=[O:19])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:26])[N:4]([CH3:27])[C:3]1=[O:28]>O>[CH3:1][N:2]1[C:7]2=[C:8]3[N:9]([C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:6]2[C:5](=[O:26])[N:4]([CH3:27])[C:3]1=[O:28])[C@H:17]([C:18]([OH:20])=[O:19])[CH2:21][CH2:22][C:23]3=[O:25]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CCC(=O)O)C(=O)O)cc2n(C)c1=O
Solvent: O
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CC[C@H]3C(=O)O
Temperature: 110 °C

Procedure:
(S)-2-(1,3-Dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)pentanedioic acid (2.44 g, 6.33 mmol) and polyphosphoric acid (4.85 ml, 6.33 mmol) were combined and heated at 110° C. for 85 mins. The reaction mixture was cooled to ˜50° C. and diluted with water to give a fluid mixture. The mixture was then cooled to room temperature, further diluted with water and extracted with chloroform (5×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1.C(N(CC)CC)C>CN1CCCC1=O>[NH2:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[CH:3]=2)[CH2:16][CH2:17]1
Reactant: Clc1cc(Nc2cnccn2)ncn1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: NCC1CCN(c2cc(Nc3cnccn3)ncn2)CC1
Temperature: 140 °C
Yield: 16.1 %

Procedure:
A mixture of 6-chloro-N-(pyrazin-2-yl)pyrimidin-4-amine (20 mg, 0.096 mmol), tert-butyl N-(4-piperidinylmethyl)carbamate (41 mg, 0.193 mmol) and triethylamine (27 μL, 0.193 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated at 140° C. for 10 minutes using microwave irradiation. The mixture was concentrated in vacuo and the residue purified using preparative HPLC. The purified solid was dissolved in dichloromethane (4 mL) and treated with trifluoroacetic acid (4 mL) for 1 hour at room temperature. The solution was applied to a MP-TsOH SPE cartridge, washed, then eluted with 2N ammonia and concentrated to give N-(6-(4-(aminomethyl)piperidin-1-yl)pyrimidin-4-yl)pyrazin-2-amine (4.4 mg, 16%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[F:51]>>[F:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccc1OCCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4F)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.093 g of 1-(4-bromobutoxy)-2-fluorobenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.28 (2:1 EtOAc-heptane); Rt=6.00.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:31])([C@@H:27]([CH3:30])[CH:28]=[CH2:29])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>C(Cl)Cl.C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:31])([C@@H:27]([CH3:30])[C@@H:28]1[O:6][CH2:29]1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: C=C[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]([C@H]1CO1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
1.360 g (6.19 mmole) of 3-chloroperoxybenzoic acid of 80% purity) were added at 0° C. to a solution of 960 mg (3.44 mmole) of (2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-penten-2-ol (which was synthesized following the procedure disclosed in Japanese Patent Provisional Publication No. Sho 60-36468) in 30 ml of methylene chloride. Five minutes after the addition, the reaction mixture was stirred, and this stirring was continued overnight at room temperature. The reaction mixture was then diluted with ethyl acetate, after which it was washed, in turn, with an aqueous solution of sodium sulfite, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride. After it had been dried, the mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, using a 1:2 by volume mixture of ethyl actate and hexane as the eluent, to afford 320 mg of stereoisomer A of the title compound (having the lower polarity), melting at 160°-180° C. and 206 mg of the desired stereoisomer B of the title compound (having the higher polarity) as an oil.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: C=CCNCC=O
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2yl isocyanate dimer (8.7 grams), the diethyl acetal of 2-allylaminoacetaldehyde (8.0 grams) and benzene (50 ml) was charged into a glass reaction flask equipped with a mechanical stirrer and thermometer. The reaction mixture was then warmed with stirring until the reactants dissolved. After this time the reaction mixture was stripped of benzene to yield an oil. This oil was dissolved in an ether-pentane mixture and was treated with diatomaceous earth and filtered. The filtrate was then stripped of solvent to yield the desired product the diethyl acetal of 2-[1-allyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde as a dark red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SCC(NC)=O.BrCC1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](C3C=CC=CC=3OC)[CH:38]=2)[NH:33]C(C)(C)C=1.CSNC(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])([CH3:20])[CH:13]=[C:12]2[CH2:21][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CNC(=O)CSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: CSNC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
2-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]-N-methylacetamide 50 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 15 mg of N-methylmercaptoacetoamide, and 58 mg of potassium carbonate reacted to give 22 mg of the title compound as a foam.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16](=O)[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1.Cl.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][NH:35][NH2:36])=[CH:32][CH:31]=1.Cl>ClCCl>[Cl:26][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]2[N:35]([CH2:34][C:33]3[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:36]=[C:16]([CH2:17][CH:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)[C:12]=12
Reactant: COc1ccc(CNN)cc1
Reactant: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(CC3COC(C)(C)O3)c3c(Cl)nc(N)nc32)cc1
Yield: 78.2 %

Procedure:
A solution of triethylamine (29.1 ml) in dichloromethane (100 ml) was added to a mixture composed of 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-one (16 g), (4-methoxybenzyl)-hydrazine hydrochloride (14.1 g) and dichloromethane (400 ml) under cooling in an ice bath over 15 minutes. After stirring under cooling in an ice bath for 1.5 hours, a 0.2 N hydrochloric acid solution (1000 ml) was added to the reaction mixture, followed by extraction with dichloromethane (400 ml). The organic layer was washed with brine (500 ml) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (16.5 g, 78%) as a solid.
Reaction SMILES: C(OC1C=C2C(=CC=1OCC=C)N=C(N1CCN(S(C3C=CC(C4C=CC=CC=4)=CC=3)(=O)=O)CC1)N=C2N)C=C.[NH2:41][C:42]1[C:51]2[C:46](=[CH:47][C:48]([O:54]C)=[C:49]([O:52]C)[CH:50]=2)[N:45]=[C:44]([Cl:56])[N:43]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[NH2:41][C:42]1[C:51]2[C:46](=[CH:47][C:48]([OH:54])=[C:49]([OH:52])[CH:50]=2)[N:45]=[C:44]([Cl:56])[N:43]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: BrB(Br)Br
Agent: C=CCOc1cc2nc(N3CCN(S(=O)(=O)c4ccc(-c5ccccc5)cc4)CC3)nc(N)c2cc1OCC=C
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(Cl)nc2cc(O)c(O)cc12
Temperature: 25 °C

Procedure:
General Procedure for the Synthesis of Sulfonamides (Scheme 4). 6,7-Bis-allyloxy-2-[4-(biphenyl-4-sulfonyl)-piperazin-1-yl]-quinazolin-4-ylamine (43): A solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (2.51 g, 10.0 mmol) in CH2Cl2 (30 mL) was cooled to −70° C. under argon, and added boron tribromide (6.01 g, 12.0 mmol). The mixture was allowed to warm up to room temperature over a period of 4 h, cooled to −70° C., added methanol (30 mL), and concentrated. The solid residue was washed with ethyl acetate to obtain 4-amino-2-chloro-6,7-dihydroxyquinazoline [1HNMR (DMSO-d6) δ 7.04 (s, 1 H), 7.51 (s, 1 H)]. A mixture of the first intermediate (0.21 g, 1.0 mmol), allyl bromide (0.432 g, 3.6 mmol) and K2CO3 (0.331 g, 2.4 mmol) in methanol (10 mL) was stirred under reflux for 12 h, concentrated, and purified by silica gel chromatography to afford 4-amino-2-chloro-6,7-diallyloxyquinazoline [1HNMR (DMSO-d6) δ 4.63 (d, J=5.4 Hz, 2 H), 4.70 (d, J=1.5 Hz, 2 H), 5.28 (d, J=1.3 Hz, 2 H), 5.42 (d, J=1.3 Hz, 1 H), 5.49 (d, J=1.3 Hz, 1 H), 6.07-6.11 (m, 2 H), 7.06 (s, 1 H), 7.62 (s, 1 H)]. A solution of the second intermediate (0.291 g, 1.0 mmol) and 1-(biphenyl-4-sulfonyl)piperazine (0.302 g, 1.0 mmol) in 1-butanol (5 mL) was stirred under reflux for 8 h, and concentrated. The solid residue was stirred with methanol under reflux for 30 min, filtered, washed with methanol to yield compound 44. 1HNMR (DMSO-d6) δ 3.36 (br s, 4 H), 4.01 (br s, 4 H), 4.60-4.64 (m, 4 H), 5.26-5.35 (m, 4 H), 6.02-6.13 (m, 2 H), 7.30-7.52 (m, 4 H), 7.72-7.75 (m, 3 H), 7.83-7.86 (m, 4 H), 8.63 (s, 1 H), 8.83 (s, 1H). HRMS (M+H)+ calcd for C30H32N5O4S 558.2169, found 558.2169. Anal. (C30H31N5O4S.HCl) C, H, N.
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-].[Cs+].[Cs+].[CH2:22](I)[CH3:23]>CC(C)=O.ClCCl>[CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O:11][CH2:22][CH3:23])=[O:10])[N:5]=[N:4][N:3]=1
Reactant: Cc1nnnn1-c1ccccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)c1ccccc1-n1nnnc1C
Temperature: 25 °C
Yield: 90.7 %

Procedure:
Under a nitrogen atmosphere, 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (89.7 g, 0.44 mol) was dissolved in acetone (1 L) and cesium carbonate (214.7 g, 0.66 mol) was added with vigorous stirring. Ethyl iodide (70.3 ml, 0.88 mol) was added dropwise and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature and filtered. The acetone was removed in vacuo to yield a yellow solid which was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate (200 ml). The organic fraction was dried (Na2SO4), filtered, and concentrated to yield 92.7 g of ethyl 2-(5-methyl-1H-tetrazol-1-yl)benzoate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:13][S:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:29]([CH2:26][CH2:27][CH3:28])[N:30]=[C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)[CH2:13][S:12][CH2:11][CH:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1C(=Cc2ccc(Cl)c(Cl)c2)CSCC1=Cc1ccc(Cl)c(Cl)c1
Reactant: CCCNN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccc(Cl)c(Cl)c3)CSCC2C1c1ccc(Cl)c(Cl)c1

Procedure:
A suspension of 6.5g of tetrahydro-3,5-bis-[(3,4-dichlorophenyl)methylene]-4H-thiopyran-4-one and 1.1g of n-propyl hydrazine in 250ml of methanol/chloroform (1:1) is heated at reflux temperature for about 16 hours. The reaction mixture is allowed to cool slightly. Unreacted starting material precipitates out and is removed by filtration. The filtrate is concentrated in vacuo, added to chloroform and washed with dilute hydrochloric acid and water. The organic layer is dried with magnesium sulfate and concentrated in vacuo to 5g of a semi-solid material. This is applied to a wet-packed (hexane) neutral alumina column (Activity I) and eluted with 0-100% ether/hexane. Elution with 10-40% ether/hexane yields the product as an oil.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2OS(C(F)(F)F)(=O)=O)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH:4]3[CH2:5][CH:1]([C:6](=[O:7])[C:8]=2[CH:13]=1)[CH:2]=[CH:3]3
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)C2CC=CC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C(=O)C1C=CC2C1
Reaction time: 18 h
Yield: 95.3 %

Procedure:
Trifluoro-methanesulfonic acid 2-(cyclopent-3-enecarbonyl)-4-methoxy-phenyl ester (19.09 g, 54.5 mmol) was dissolved in DMF (100 mL) under a N2 atmosphere and treated with diisopropylethylamine (10.6 g, 82.0 mmol), potassium acetate (1.07 g, 11.0 mmol) and 1,3-bis(diphenylphosphino)propane (2.25 g, 5.46 mmol). This mixture was stirred and degassed (3 vacuum/N2 purge cycles) then treated with palladium acetate (0.49 g, 2.18 mmol). After stirring 20 min. the mixture was warned to 120° C. for 18 hours, cooled and poured into brine (300 mL). The resulting mixture was extracted with EtOAc (4×100 mL) and the combined organic layer was washed with a sat. aq. NaHCO3 soln. (100 mL), H2O (100 mL), brine (100 mL), dried (MgSO4), filtered, concentrated and chromatographed on silica gel to provide an oil (10.4 g, 95%). (elute w/7% EtOAc/hexanes). 1H NMR (CDCl3) δ 7.41 (d, J=2.8 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.88 (dd, J=8.0, 2.8 Hz, 1H), 6.72 (dd, J=5.2, 3.0 Hz, 1H), 6.06 (dd, J=5.2, 3.2 Hz, 1H), 3.77 (s, 3H), 3.60 (dd, J=4.3, 3.2 Hz, 1H), 3.44 (dd, J=5.0, 3.4 Hz, 1H), 2.65 (AB m, 1H), 2.56 (br AB d, J=10.5 Hz, 1H). 13C NMR (CDCl3) 196.11, 158.87, 145.90, 140.34, 130.295, 129.94, 126.14, 119.42, 111.90, 55.61, 55.48, 49.08, 45.97. GCMS m/e 200 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH:16]1([CH:19]=O)[CH2:18][CH2:17]1.C>>[CH:16]1([CH2:19][N:1]2[CH2:6][CH2:5][CH2:4][C:3]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:2]2)[CH2:18][CH2:17]1
Reactant: O=CC1CC1
Reactant: O=C1Nc2ccccc2C12CCCNC2
Agent: C
Product: O=C1Nc2ccccc2C12CCCN(CC1CC1)C2
Yield: 90 %

Procedure:
The compound was prepared according to PROCEDURE 1, Method A by reaction of spiro[indoline-3,3′-piperidin]-2-one with 3 equiv. of cyclopropanecarboxaldehyde. Yield: 90%. 13C NMR (CDCl3): δ 3.8, 4.0, 8.3, 21.4, 31.8, 48.6, 53.3, 58.4, 63.6, 109.7, 121.7, 126.1, 127.4, 134.7, 140.0, 182.2; MS (CI, CH4): m/z (rel. int.) 257 (M+1, 100).
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:20][C:21]([OH:23])=[O:22])([CH3:19])[C:9]([O:11][Si](C(C)(C)C)(C)C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]1([CH2:7][C:8]([CH2:20][C:21]([OH:23])=[O:22])([CH3:19])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CC(=O)O)(Cc1ccccc1)C(=O)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(CC(=O)O)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 3-phenyl-2-methylcarboxymethylpropionic acid, t-butyldimethylsilyl ester (3.07 g, 9.13 mmol) in tetrahydrofuran (11 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between ethyl ether and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter and evaporate the solvent in vacuo to give 3-phenyl-2-methylcarboxymethylpropionic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11](=O)[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a stirred solution of (1-carbamoyl-cyclopropyl)-carbamic acid tert-butyl ester (5.7 g, 28.4 mmol) in DMF (50 mL) was added cyanuric chloride (2.6 g, 14.2 mmol) and it was stirred at room temperature for 1 h before it was diluted with water (400 mL). The product precipitated and filtration gave (1-cyano-cyclopropyl)-carbamic acid tert-butyl ester (2.79 g, 53.9%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].CS(C)=O.[CH3:10][N:11]([O:16][CH3:17])[C:12](=[O:15])[CH2:13]Cl>C(Cl)Cl>[CH3:10][N:11]([O:16][CH3:17])[C:12](=[O:15])[CH2:13][O:3][C:1](=[O:4])[CH3:2]
Reactant: CON(C)C(=O)CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)COC(C)=O
Temperature: 70 °C
Reaction time: 7 h
Yield: 75.2 %

Procedure:
A mixture of 23 g (0.28 mole) of sodium acetate, 200 ml of dimethylsulphoxide and 34.4 g (0.25 mole) of chloroacetic acid N-methyl-N-methoxy-amide (for its preparation, see DE-OS (German Published Specification) No. 2,753,182) was stirred at 70° C. for 7 hours. The mixture was then cooled to room temperature, 500 ml of methylene chloride were added and the inorganic salt was filtered off. The filtrate was evaporated in vacuo and the residue was distilled. 30.3 g (75% of theory) of acetoxyacetic acid N-methyl-N-methoxy-amide were thus obtained as a colourless liquid with a boiling point of 70° C./0.3 mm Hg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: O=C1N(CC2CCCCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.28 g, 1.0 mmol), 2-(bromomethyl)tetrahydro-2H-pyran (0.36 g, 2.0 mmol) and cesium carbonate (1.00 g, 3.0 mmol) was stirred in butanone at 80° C. for 3 h. Upon cooling to ambient temperature, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography with ethyl acetate-hexanes (1:5-1:1) to afford 1′-(tetrahydro-2H-pyran-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.31 g, 82%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.38-6.94 (m, 4H), 6.47 (d, J=2.9 Hz, 1H), 6.38 (s, 1H), 4.79 (ABq, 2H), 4.50 (t, J=8.6 Hz, 2H), 4.01-3.61 (m, 4H), 3.37 (t, J=11.1 Hz, 1H), 2.97 (t, J=8.4 Hz, 2H), 1.97-1.27 (m, 6H); 13C NMR (75 MHz, CDCl3) δ178.1 (2C), 161.7 (2C), 161.3, 161.2, 143.2, 143.1, 132.8, 132.7, 128.6 (2C), 123.5, 123.1, 123.1, 120.6, 120.5, 119.8 (2C), 119.0, 118.9, 109.7, 93.2, 93.1, 80.6, 75.7, 75.5, 72.3, 68.4 (2C), 57.7, 57.6, 45.8, 45.7, 29.6, 29.5, 29.1, 25.8, 23.0; MS (ES+) m/z 378.3 (M+1).