Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](O)=O)[C:3]=1[OH:11].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19]>>[OH:11][C:3]1[C:2]([NH2:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[S:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: Nc1ccccc1S
Reactant: Nc1cccc(C(=O)O)c1O
Product: Nc1cccc(-c2nc3ccccc3s2)c1O

Procedure:
2(2'-hydroxy-3'-aminophenyl)benzothiazole was prepared by reacting 3-aminosalicylic acid with o-aminobenzenethiol according to the process of Example I. At the end of 6 hours the desired product precipitated and said product was filtered and air-dried.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:22]2[S:44][C:25]3=[N:26][C:27]([N:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:28][C:29](=[O:30])[N:24]3[N:23]=2)[CH:7]=[C:8]([NH:10][C:11](=[O:21])[CH2:12][NH:13]C(OC(C)(C)C)=O)[CH:9]=1)(=[O:3])[CH3:2].C(OC(NCC(NC1C=C(C2SC3=NC(N4CCN(C(OC(C)(C)C)=O)CC4)=CC(=O)N3N=2)C=C(C(O)C)C=1)=O)=O)(C)(C)C.[BH4-].[Na+]>>[NH2:13][CH2:12][C:11]([NH:10][C:8]1[CH:7]=[C:6]([C:22]2[S:44][C:25]3=[N:26][C:27]([N:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]4)=[CH:28][C:29](=[O:30])[N:24]3[N:23]=2)[CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1)=[O:21]
Reactant: CC(=O)c1cc(NC(=O)CNC(=O)OC(C)(C)C)cc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)c1
Agent: CC(O)c1cc(NC(=O)CNC(=O)OC(C)(C)C)cc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(NC(=O)CN)cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1

Procedure:
The compound of this example is prepared as described in Example 13 above except that the acetyl group of tert-butyl 4-(2-(3-acetyl-5-(2-((tert-butoxycarbonyl)amino)-acetamido)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate is further reduced to tert-butyl 4-(2-(3-(2-((tert-butoxycarbonyl)amino)acetamido)-5-(1-hydroxyethyl)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate using sodium borohydride. The resulting product is then deprotected as described in Step 6 of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.95-8.80 (br.s., 2H), 8.16 (t, J=1.8 Hz, 1H), 8.16-8.07 (br.s., 2H), 7.76 (t, J=1.8 Hz, 1H), 7.59 (s, J=1.8 Hz, 1H), 5.61 (s, 1H), 5.50-5.45 (br.s., 1H), 4.83 (q, J=6.7 Hz, 1H), 3.81 (s, 2H), 3.78 (t, J=5.2 Hz, 4H), 3.19 (t, J=5.2 Hz, 4H), 1.36 (d, J=6.7 Hz, 3H); LC/MS: tR=2.417 min; HRMS: m/z (M+H+)=(Calculated for C19H24N7O3S=430.1661).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNS(=O)(=O)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-fluorobenzenesulfonyl chloride: ESMS m/e: 462.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8]1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1>C1COCC1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:14]=3)[CH2:11][CH2:12]2)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 551.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([C:12]([O:14]C)=O)=[N:9][N:8]=2)[CH:2]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]([C:10]2[O:11][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:8][N:9]=2)=[O:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1nnc(-c2cccnc2)o1
Reactant: BrCCCCCCc1ccccc1
Product: O=C(CCCCCCc1ccccc1)c1nnc(-c2cccnc2)o1
Yield: 34 %

Procedure:
Starting with methyl 5-(pyridin-3-yl)-[1,3,4]-oxadiazole-2-carboxylate and 6-bromohexylbenzene, the title compound (20 mg, 34%) was obtained as a white solid, using a procedure analogous to that described in Example 1. 1H NMR (400 MHz, CDCl3) 1.44 (m, 4H), 1.66 (quintet, J=7.5 Hz, 2H), 1.82 (quintet, J=7.3 Hz, 2H), 2.63 (dd, J=7.9, 7.3 Hz, 2H), 3.21 (t, J=7.4 Hz, 2H), 7.17-7.19 (m, 3H), 7.26-7.30 (m, 2H), 7.52 (ddd, J=7.9, 4.7, 0.6 Hz, 1H), 7.94 (dt, J=7.9, 1.9 Hz, 1H) 8.85 (dd, J=5.0, 1.8 Hz, 1H), 9.41 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 23.6, 28.8, 28.9, 31.2, 35.8, 35.9, 40.0, 119.4, 123.9, 125.6, 128.2, 128.4, 134.9, 142.6, 148.7, 153.4, 161.0, 164.3, 187.3; MALDI-FTMS m/z 336.1716 (C20H21N3O2+H+ requires 336.1706).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.[OH:20]O>C(O)(=O)C.N>[NH2:1][C:2]1[N+:3]([O-:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:16])[F:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: OO
Reactant: COc1cc(-c2ccc(N)nn2)ccc1OC(F)F
Agent: N
Solvent: CC(=O)O
Product: COc1cc(-c2ccc(N)[n+]([O-])n2)ccc1OC(F)F
Temperature: 0 °C
Yield: 85.4 %

Procedure:
20.0 g (74.8 mmol) of 3-amino-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine are dissolved in 100 ml of glacial acetic acid and, while stirring, 30.6 ml (300 mmol) of 30% strength hydrogen peroxide are added, and the mixture is stirred at 80° C. for 2.5 h. The reaction solution is diluted with 1 kg of ice and 200 ml of concentrated ammonia solution, and the precipitate which has formed is collected on a suction funnel, washed first with water and then with ethanol and petroleum ether (b.p. 40°-70° C.) and dried at 75° C. in vacuo. 18.1 g (85.4%) of the title compound of m.p. 214° C. are obtained.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)[OH:6].N[C@@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14]>>[C:16]([OH:18])(=[O:17])[C@@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[OH:6]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)C[C@@H](O)C(=O)O
Reaction time: 0.25 h

Procedure:
While heating and stirring 100 ml of aqueous solution of 14 g of sodium nitrite at 90° C., 400 ml aqueous solution of 0.5N sulfuric acid of 25 g of D-leucine was added over 45 minutes. After dripping, the solution was stirred for 15 minutes until foams were no longer generated. The reaction solution was concentrated to 200 ml in vacuo, and the obtained residue was extracted with diethyl ether. The diethyl ether layer was washed one with 1N hydrochloric acid, and twice with saturated brine sequentially, and dried over sodium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was left over, crystallized, and the captioned compound was obtained. Yield: 14.50 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:36])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)[CH2:13][C@H:12]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:36])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=3)[CH2:13][C@H:12]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(c2ccc(C(=O)O)cn2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 10 h
Yield: 99.9 %

Procedure:
To a solution of the compound (0.500 g) obtained in Example 478 in methanol (6 mL) was added 1N aqueous sodium hydroxide solution (2.74 mL), and the mixture was stirred for 10 hr. The reaction mixture was concentrated, the residue was made neutral with 1N hydrochloric acid, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 30→100% ethyl acetate/hexane) to give the title compound (0.474 g, 100%) as a white powder.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].C(O[C:13]1([CH3:23])[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2)(=O)C(C)=C.C12(O)CC3CC(CC(C3)C1)C2>CCCCCC>[CH2:23]=[C:13]1[CH:14]2[CH2:22][CH:18]3[CH2:17][CH:16]([CH2:21][CH:20]1[CH2:19]3)[CH2:15]2
Reactant: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Agent: O=S(=O)([O-])[O-]
Agent: OC12CC3CC(CC(C3)C1)C2
Agent: [Mg+2]
Solvent: CCCCCC
Product: C=C1C2CC3CC(C2)CC1C3
Reaction time: 3 h

Procedure:
A reaction, a post-treatment, etc. were conducted in the same operation as in Example 16 except that no magnesium sulfate was used, hexane was used as a solvent, and the reaction was conducted at a refluxing temperature for 3 hours. 1.0 g of a crude product was obtained. However, the yield of 2-methyl-2-adamantyl methacrylate was 31%, the raw material adamantanol remained by 22%, and 2-methyleneadamantane was formed by 46%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:54](O)=[O:55])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][C@H:48]([CH3:52])[CH2:47]2)=[CH:42][C:41]3=[O:53])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN(C(C)C)C(C)C.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>CC(N(C)C)=O>[F:30][C:28]1[CH:27]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:54]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)=[O:55])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][C@H:48]([CH3:52])[CH2:47]2)=[CH:42][C:41]3=[O:53])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4cc(F)cc(F)c4)c3o2)CCO1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N4CCOCC4)cc(C4CCCN4c4cc(F)cc(F)c4)c3o2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
TBTU (154 mg, 0.48 mmol) was added to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (90 mg, 0.19 mmol), DIPEA (0.083 mL, 0.48 mmol) dissolved in DMA (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 30 min. Morpholine (0.050 mL, 0.57 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-4H-chromen-4-one (68 mg, 66%) as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH2:2].CC(C)([O-])C.[Na+].Br[C:16]1[C:24]2[NH:23][C:22]3[CH:25]4[CH2:31][CH2:30][N:28]([CH2:29][C:21]=3[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH2:27][CH2:26]4.S([O-])([O-])(=O)=O.[Mg+2]>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3](/[CH:1]=[CH:2]/[C:16]2[C:24]3[NH:23][C:22]4[CH:25]5[CH2:31][CH2:30][N:28]([CH2:29][C:21]=4[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:27][CH2:26]5)[CH:4]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: C=Cc1cccnc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1cccnc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
A mixture of bis(tri-t-butylphosphino)palladium (18.4 mg, 0.036 mmol; Strem), 3-vinylpyridine (123 mg, 0.52 mmol; TCI-US), sodium t-butoxide (87 mg, 0.90 mmol; Aldrich) and the product of Example 1B (105 mg, 0.36 mmol) was combined with 1,4-dioxane (2 mL). The mixture was purged with a stream of nitrogen for 2 minutes, then stirred at 85° C. in a sealed tube. After 18 hours, the reaction mixture was cooled to ambient temperature. Magnesium sulfate (43 mg, 0.36 mmol) and 3-vinylpyridine (85 mg, 0.36 mmol; TCI-US) were added and the reaction mixture was again purged with nitrogen, sealed and stirred at 100° C. for 24 hour in a sealed tube. The reaction mixture was cooled to ambient temperature, filtered through a glass microfiber frit, rinsed with methanol (2 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 30-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.01-2.18 (m, 4 H), 3.02-3.12 (m, 2 H), 3.14 (pent, J=3.4 Hz, 1 H), 3.20-3.29 (m, 2 H), 4.23 (s, 2 H), 7.03 (t, J=7.6 Hz, 1 H), 7.25 (d, J=16.5 Hz, 1 H), 7.27 (d, J=7.3 Hz, 1 H), 7.41 (d, J=7.3 Hz, 1 H), 7.43 (dd, J=8.2, 4.9 Hz, 1 H), 7.74 (d, J=16.5 Hz, 1 H), 8.07-8.15 (m, 1 H), 8.38 (dd, J=4.6, 0.9 Hz, 1 H), 8.75 (d, J=1.5 Hz, 1H); MS (APCI) m/z 316 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[N+:21]([O-])=O)[CH:7]=1.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1
Reactant: COc1ccc(F)cc1-c1c([N+](=O)[O-])cnn1CCOC[Si](C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)cc1-c1c(N)cnn1CCOC[Si](C)(C)C
Temperature: 75 °C
Reaction time: 6 h
Yield: 70.2 %

Procedure:
To a solution of 5-(5-fluoro-2-methoxyphenyl)-4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazole (1.0 g, 2.7 mmol) in 8 mL ethanol was added 16 mL water, ammonium chloride (570 mg, 10.8 mmol), and iron powder (760 mg, 13.5 mmol). The reaction mixture was stirred at 75° C. for 6 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was added to 150 mL saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 640 mg (70%) of 5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine, which was carried forward without purification. LCMS (ESI) m+H=338.1. 1H NMR (400 MHz, CDCl3) δ: 7.37 (m, 2H), 7.20 (t, 1H), 7.04 (dd, 1H), 5.42 (t, 2H), 3.90 (d, 3H), 3.65 (t, 2H), 0.96 (t, 2H), 0 (s, 9H).
Reaction SMILES: [Li+].[OH-:2].[CH2:3]([N:9]([CH3:20])[C:10]([CH:12]1[CH2:17][CH:16]2[CH2:18][CH:13]1[C:14](=[O:19])[O:15]2)=[O:11])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].Cl>>[CH2:3]([N:9]([CH3:20])[C:10]([CH:12]1[CH2:17][CH:16]([OH:15])[CH2:18][CH:13]1[C:14]([OH:2])=[O:19])=[O:11])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: [OH-]
Reactant: C=CCCCCN(C)C(=O)C1CC2CC1C(=O)O2
Agent: Cl
Agent: [Li+]
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)O
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of LiOH (105 mg in 4 mL, of water) was added at 0° C. to the lactone amide (65). After 1 h, the conversion was completed (HPLC). The mixture was acidified to pH 2-3 with 1N HCl, extracted with EtOAc, dried (MgSO4), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give the title compound (520 mg, 88%), m/z=270 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:24]=2[C:25]([NH:27][CH2:28][C:29]#[CH:30])=[O:26])[C:19]([Cl:36])=[CH:18][N:17]=1>>[Cl:36][C:19]1[C:20]([NH:22][C:23]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:24]=2[C:25]([NH:27][CH2:28][C:29]#[CH:30])=[O:26])=[N:21][C:16]([NH:14][C:12]2[CH:11]=[CH:10][C:9]3[N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]=3[CH:13]=2)=[N:17][CH:18]=1
Reactant: CCN1CCCOc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3CC)ncc1Cl

Procedure:
2-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (50 mg, 20%). LCMS (m/e) 495 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.05 (s, 1H), 7.40-7.23 (m, 3H), 7.09 (s, 1H), 6.93 (s, 1H), 6.87 (d, 1H, J=8.6 Hz), 6.69 (d, 1H, J=8.6 Hz), 6.51-6.42 (m, 1H), 4.16-4.07 (m, 2H), 4.06 (t, 2H, J=5.2 Hz), 3.23-3.11 (m, 4H), 2.24-2.19 (m, 1H), 2.04-1.94 (m, 2H), 1.18 (t, 3H, J=7.1 Hz).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:17]#[N:18]>C(O)C>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:22][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[OH:13])[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: N#Cc1ccc(N)c(O)c1
Solvent: CCO
Product: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Yield: 53.5 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (1.2 mL, 8.12 mmol) and 3-hydroxy-4-aminobenzonitrile (1.25 g, 8.11 mmol) in ethanol was heated at 85° C. for overnight. A tan precipitates forms. The solid was filtered, and collected. 1.12 g (53%) of 3-ethoxy-4-(2-hydroxy-4-cyanoanilino)-3-cyclobutene-1,2-dione was obtained. LC/MS(H+) 259
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]1[C:20]2[C:21](=O)[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[S:25][C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[CH:15]1[C:20]2[C:21](=[S:2])[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[S:25][C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: c1ccncc1
Product: S=C1Nc2ccccc2Sc2ccccc21

Procedure:
Phosphorus pentasulphide (1.2 eq) was added to a solution of 10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (1.14 g, 5 mmol) in pyridine (40 ml) and heated under reflux for 15 hr. The mixture was allowed to cool and poured into hydrochloric acid (1.3M) at 0° C. Filtration of the yellow precipitate and purification by chromatography on silica (eluting with dichloromethane/methanol, 99:1) followed by recrystallisation from ethanol gave the title compound as yellow crystals (700 mg, m.p. 245°-246° C., Rf 0.81, CH2Cl2/MeOH9:1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=O)[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:36][NH:37][CH3:38].C(N(C(C)C)CC)(C)C>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:31])[N:37]([CH3:38])[CH3:36])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and dimethylamine hydrochloride/diisopropylethylamine Rf value: 0.5 (silica gel, methylene chloride/methanol=5:1) C30H32N4O2
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:5]([NH:8][C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:32])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:5]([NH:8][C:9](=[S:42])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(Br)cnc(NC(=O)Cc2ccc(S(C)(=O)=O)cc2)c1-c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: Cc1c(Br)cnc(NC(=S)Cc2ccc(S(C)(=O)=O)cc2)c1-c1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 60.7 %

Procedure:
To a suspension of N-[5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-2-(4-methanesulfonyl-phenyl)-acetamide (Int. 10, 305 mg, 0.579 mmol) in toluene (15 mL) was added Lawesson's reagent (234 mg, 0.579 mmol) and the reaction mixture was heated at 110° C. for 24 hrs. A further amount of Lawesson's reagent (351 mg) was added and heating was continued for 2.5 hrs before a final addition of Lawesson's reagent (234 mg) was made. The reaction mixture was heated for 19 hrs then cooled, concentrated in vacuo and the resultant residue purified by flash chromatography eluting with a gradient of 0-50% ethyl acetate in cyclohexane to give the title compound as an orange glass (191 mg).
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:14])=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:14][CH2:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: OCc1nccc2c1OCO2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1nccc2c1OCO2

Procedure:
2-Hydroxymethyl-3,4-methylenedioxypyridine (90 mg, 0.59 mmol) was dissolved in methylene chloride (10 ml) and thionyl chloride (240 mg, 2 mmol) was added. After 10 min at ambient temperature the mixture was hydrolysed with sodium hydrogen carbonate and the phases were separated. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 90 mg (88%) of the title compound (crude).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].C(Cl)(=O)C(Cl)=O.[NH3:30]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([NH2:30])=[O:8]
Reactant: N
Reactant: COC(=O)c1cc(I)ccc1OCc1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Product: NC(=O)c1cc(I)ccc1OCc1ccc2ccccc2c1

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene was reacted with methyl 5-iodosalicylate to give methyl 5-iodo-2-(naphth-2-ylmethoxy)benzoate (68%). Using conventional procedures the ester was hydrolysed with base to give the corresponding acid; the acid chloride was prepared by reaction with oxalyl chloride; and the acid chloride was reacted with ethanolic ammonia to give 5-iodo-2-(naphth-2-ylmethoxy)benzamide (84% from the ester), m.p. 163° C. The benzamide so obtained was reacted with trifluoroacetic anhydride in the presence of pyridine and dimethoxyethane as reaction solvent. There was thus obtained 3-cyano-4-(naphth-2-ylmethoxy)phenyl iodide (72%), m.p. 108°-110° C.