Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)[C@H]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18]O)O[C@H](CO)[C@@H](O)[C@@H:10]2O)[C@H:5]([OH:20])[C@@H:4](O)[C@@H:3]1O.C1C2C(=CC=CC=2)C=CC=1.C(OC(C)C)(=O)C(C)O>CC(O)C>[OH:20][CH:5]([CH:4]=[CH2:3])[C:6]([O:8][CH:9]([CH3:18])[CH3:10])=[O:7]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: CC(C)OC(=O)C(C)O
Solvent: c1ccc2ccccc2c1
Solvent: CC(C)O
Product: C=CC(O)C(=O)OC(C)C
Temperature: 160 °C
Yield: 36.1 %

Procedure:
An autoclave (50 cc microclave) is charged with 8.0 g of 2-propanol, 0.2249 g of sucrose (0.6569 mmol), 119.7 mg naphthalene (internal standard) and finally with 159.7 mg Sn-BEA (prepared according to U.S. Pat. No. 6,306,364). The autoclave is closed, charged with 20 bar of argon and heated to 160° C. After the temperature reaches 100° C., the mechanical stirrer is started (500 rpm) and the mixture is heated for 20 hours under these conditions. GC-analysis of the reaction mixture shows that 0.68 mmol of isopropyl lactate is formed (26%) together with 0.237 mmol isopropyl 2-hydroxy-3-butenoate (12%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][C:19]([CH3:25])=[C:20]([C:22]([OH:24])=[O:23])[N:21]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CN.CN(C(ON1N=N[C:42]2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][C:19]([CH3:25])=[C:20]([C:22]([O:24][CH2:41][CH3:42])=[O:23])[N:21]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1sc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)nc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)sc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylic acid (25b) was dissolved in DMF (10 mL), to it methanamine (1 equiv.) was added followed by the addition of HATU (1.5 equiv.) and DIPEA (4 equiv.) and stirred for 3 h at room temperature. The reaction mixture was concentrated to remove DMF under reduced pressure. The crude material obtained was purified by flash column chromatography using silica gel and MeOH:CHCl3 as eluent. The material obtained was triturated with diethyl ether and hexane to afford ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.32 (d, J=6.40 Hz, 6H), 2.73 (s, 3H), 2.81 (d, J=4.40 Hz, 3H), 3.64-3.69 (m, 1H), 6.13 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.13 (d, J=4.80 Hz, 1H), 8.20 (d, J=7.20 Hz, 1H), 8.37 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.33 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.606 min; LCMS (ES-API), m/z 439.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.323 min; Purity: 96.3%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Sn](C)(C)C)[CH:5]=[C:4]([CH3:12])[N:3]=1.Br[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][N:21]2[CH:24]2[CH2:26][CH2:25]2)=[CH:16][C:15]=1[F:33].CN(C)P(N(C)C)(N(C)C)=O>O1CCOCC1.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>[CH:24]1([N:21]2[C:22]3[C:17](=[CH:16][C:15]([F:33])=[C:14]([C:6]4[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:12])[CH:5]=4)[CH:23]=3)[C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(Br)c(F)cc2c1=O
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O

Procedure:
2,6-Dimethyl-4-(trimethylstannyl)pyridine (part g (10.1 g) and 1.52 g dichlorobis(triphenylphosphine)-palladium was added to a stirred solution of 12.13 g ethyl 7-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (part f) and 10 ml hexamethylphosphoramide (HMPA) in 240 ml dioxane under nitrogen. The reaction mixture was heated under reflux for 24 hours, then cooled and partitioned between water and methylene dichloride. The organic extract was washed with sodium chloride solution, dried (magnesium sulfate) and concentrated to give 12.0 g ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, m.p. 198°-200° C.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>[Hg]>[CH2:18]([Si:2]([Cl:4])([Cl:3])[Cl:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: C=CCCCCCCCCCCC=C
Reactant: Cl[SiH](Cl)Cl
Agent: [Hg]
Product: C=CCCCCCCCCCCCC[Si](Cl)(Cl)Cl
Yield: 30.3 %

Procedure:
A stirred mixture of 6.8 g (0.05 mole) trichlorosilane and 19.6 g (0.1 mole) 1,13-tetradecadiene was irradiated in a closed quartz tube at 45° C. for 72 hours with two Hanau 70 watt high pressure mercury immersion lamps, emitting a broad spectrum of ultraviolet light. The resulting crude product was then fractionated to yield 5 g (25%) of 13-tetradecenyl trichlorosilane as the monoadduct.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:32][C:33]([C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][CH2:38][C@H:39]2[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[NH:34]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH2:13][C:14]1[O:16][N:34]=[C:33]([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][CH2:38][C@H:39]3[NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[N:32]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C(=N)NO)cccc21
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1OCC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared using General Procedure 2. A solution of 2-(3,4-diethoxyphenyl)acetic acid (150.0 mg, 0.67 mmol) in DMF (3 mL) was treated with HOBt (164.8 mg, 1.22 mmol) and EDC (172.7 mg, 0.9 mmol) at room temperature. The reaction was stirred for 2 h until the complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-54 (233.8 mg, 0.8 mmol) was added and stirred at room temperature for 2 h and then mixture was heated to 80° C. for 16 h. The reaction was diluted with NaHCO3 (10 mL) and extracted with EA (3×10 ml). The organic phase was dried over MgSO4 and the crude product was purified by a chromatography (EA/hexanes) to produce (R)-tert-butyl 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-56 (187 mg, 58%) as off-white solid and used directly in the next step. LCMS-ESI (m/z) calculated for C27H33N3O5: 479.2; found 502.2 [M+Na]+, tR=4.11 min. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 6.81 (ddd, J=20.2, 12.8, 5.1 Hz, 3H), 5.18 (d, J=8.4 Hz, 1H), 4.69 (d, J=8.3 Hz, 1H), 4.15 (d, J=6.1 Hz, 2H), 4.06-3.93 (m, 4H), 3.32 (ddd, J=17.4, 8.8, 3.4 Hz, 1H), 3.14-2.91 (m, 1H), 2.65-2.40 (m, 1H), 1.75 (dq, J=12.9, 8.4 Hz, 1H), 1.36 (ddd, J=40.2, 26.9, 22.6 Hz, 15H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:24]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][S:24]4(=[O:31])=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 73 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 127 and [1,2]thiazinane 1,1-dioxide (68 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (157 mg) was obtained.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([CH3:33])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][NH2:32]>>[C:25]1([CH3:33])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:32]1
Reactant: Cc1ccccc1NN
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Product: Cc1ccccc1-n1nccc1-c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and o-tolylhydrazine according to the method described for example 1. MS: M=397.1 (M+H)+
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:29]1([CH2:36][CH2:37][C:38]2[S:42][C:41]([C:43]([O-])=O)=[CH:40][CH:39]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Li+]>>[N:29]1([CH2:36][CH2:37][C:38]2[S:42][C:41]([CH2:43][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:40][CH:39]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C([O-])c1ccc(CCN2CCCCCC2)s1
Agent: [Li+]
Product: CCN(Cc1ccc(CCN2CCCCCC2)s1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 86.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and lithium 5-(2-azepan-1-ylethyl)thiophene-2-carboxylate (110 mg) according to an analogous synthetic method to Example 152, the title compound (47 mg) was obtained.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.Br[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=1[Cl:22]>>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=1
Reactant: Clc1cncc(Cl)c1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Product: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)cncc2Cl)n1

Procedure:
This example was synthesized from 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol and 4-(bromomethyl)-3,5-dichloropyridine by following general procedure as described in the last step of Example 22. The title compound was obtained as a white solid (660 mg, 37% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.72 (s, 2H), 6.69 (br, 1H), 8.64 (s, 2H); M+356.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[CH2:23][CH2:22][C:21](=[O:24])[C:9]3=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:41](O)(=[O:52])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH2:51]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:41]([O:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([N:2]([CH3:25])[CH3:1])[CH:12]=3)[CH:7]=[C:8]3[CH2:23][CH2:22][C:21](=[O:24])[C:9]=23)=[CH:18][CH:17]=1)(=[O:52])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH2:51]
Reactant: C=CCCCCCCCCC(=O)O
Reactant: CN(C)c1ccc2cc3c(c(-c4ccc(CO)cc4)c2c1)C(=O)CC3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OCc1ccc(-c2c3c(cc4ccc(N(C)C)cc24)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
An oven-dried, 25 mL one-necked round-bottomed flask was charged with compound 15b (0.021 g, 0.060 mmol), DCC (0.014 g, 0.069 mmol), DMAP (0.008 g, 0.069 mmol) and dry CH2Cl2 (7 mL). 10-Undecenoic acid (0.012 mL, 0.060 mmol) was added and the mixture was stirred at rt overnight. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:9). After filtration over a short pad of celite, the reaction was quenched with sat'd aq NaHCO3 solution (30 mL). The layers were separated and the aqueous phase was extracted with Et2O (3×15 mL). The combined organic layers were washed with brine (2×40 mL), dried over MgSO4, gravity filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 1.5:8.5, to provide 0.018 g of the title compound as a yellow solid in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccc(Cl)c3)cc2)c2ccc3ccccc3c2N1
Yield: 52.2 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.063 mmol) obtained in Example 1, (3), and 3-chlorobenzoyl chloride (17 mg, 0.095 mmol), the title compound (15 mg, yield 52%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(=O)C)[N:6]=[CH:5]2>CO.Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CCc1c(Br)ccc2c1cnn2C(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1c(Br)ccc2[nH]ncc12

Procedure:
A mixture of 3.78 g of the compound prepared in Example 212c in 7.3 ml methanol and 26.3 ml of 37% hydrochloric acid was heated under reflux for 2 hours. This was then diluted with 400 ml ethyl acetate. The organic phase was washed three times with 50 ml portions of sodium hydrogen carbonate solution and once with 50 ml saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The crude product thus obtained was purified by column chromatography on silica gel with hexane/0-50% ethyl acetate. Yield: 2.97 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:32])([CH3:31])[C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:19]3([CH2:23][O:22][C:21]([NH2:24])=[N:20]3)[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:17]=3)[O:12][C:9]2=[CH:10][CH:11]=1.[H][H]>[Pd].C(CC(OC)=O)C>[CH3:1][O:2][C:3]([CH3:32])([CH3:31])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:19]3([CH2:23][O:22][C:21]([NH2:24])=[N:20]3)[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:17]=3)[O:12][C:9]2=[CH:10][CH:11]=1
Reactant: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cccnc3)cnc1O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCC(=O)OC
Product: COC(C)(C)CCc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cccnc3)cnc1O2
Yield: 49.6 %

Procedure:
To a solution of 7-(3-methoxy-3-methylbut-1-ynyl)-3-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (110 mg, 0.258 mmol) in 1:1 methanol ethyl acetate (10 mL) was added Pd/C (5%) (274 mg, 2.58 mmol). The resulting slurry was maintained under 1 atm of hydrogen gas for 4 hours at which point another loading of Pd/C (5%) (274 mg, 2.58 mmol) was added and the reaction was maintained under 1 atm of hydrogen gas for an additional 3 hours. The reaction was filtered through a pad of celite, washing well with methanol and ethyl acetate. The derived mixture was filtered through a 0.1 micron frit and concentrated to provide 7-(3-methoxy-3-methylbutyl)-3-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (55 mg, 0.128 mmol, 49.5% yield) as a light yellow solid. MS m/z=431.2 [M+H]+. Calc'd for C25H27N4O3: 431.2.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][C:24]=2[O:23]1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]3[O:32][CH2:22][O:23][C:24]=3[CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccc2c(c1)OCO2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.29 g--see Preparation 3), 3,4-methylenedioxybenzyl chloride (0.18 g--commercially available), sodium bicarbonate (0.1 g) and acetonitrile (20 ml) was heated under reflux for 3 hours. The mixture was partitioned between dichloromethane and 10% aqueous sodium carbonate, the layers separated and the dichloromethane layer dried (MgSO4). The solution was concentrated in vacuo and the residue purified by column chromatography on silica, eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.22 g.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][N:18]=2)=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[NH2:25][C:26]([NH2:28])=[S:27].C([O-])(=O)C.[Na+]>C(O)C>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH:2]3[S:27][C:26](=[NH:25])[NH:28][C:3]3=[O:4])=[CH:9][CH:10]=2)=[N:18][CH:19]=1)[CH3:24]
Reactant: CCc1ccc(CCOc2ccc(CC(Br)C(=O)OC)cc2)nc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(CCOc2ccc(CC3SC(=N)NC3=O)cc2)nc1

Procedure:
A mixture of methyl 2-bromo-3-(4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)propionate (28.4 g), thiourea (5.5 g), sodium acetate (6 g) and ethanol (200 ml) is heated to reflux under heating for three hours. The mixture is concentrated and the concentrate is neutralized with saturated solution of sodium hydrogencarbonate. Adding water (80 ml) and ether (40 ml) precipitates a solid from the mixture. Filtering off gives beige-coloured crystalline
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[OH:35][CH:36]1[CH2:40][CH2:39][CH:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37]1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:12]([O:35][CH:36]4[CH2:40][CH2:39][CH:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: CCOC(=O)C1CCC(O)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Temperature: 80 °C

Procedure:
To a solution of 5-(biphenyl-4-yl)-6-chloro-2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Intermediate 3, 0.350 g, 0.682 mmol) and ethyl 3-hydroxycyclopentanecarboxylate (Intermediate 9, 0.647 mL, 4.09 mmol) in 2.3 mL DMF was added DSU (0.514 mL. 3.41 mmol) dropwise via syringe. The reaction was heated overnight at 80° C., then diluted with EtOAc, and washed with H2O and brine. The aqueous layer was further extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by preparative TLC (25% EtOAc/hexanes) furnished the desired compound as a pale yellow oil. LCMS: calculated for C33H39ClN2O4Si 591.21, observed m/e 591.04 M+ (Rt 3.06/4 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=2)[N:10]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([CH:32]=1)[NH2:31].C[Al](C)C>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([NH:31][C:19](=[O:21])[C:18]2[CH:23]=[CH:24][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][CH:17]=2)[CH:32]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: C[Al](C)C
Product: Cc1ccc(Cl)cc1NC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 46.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 5-chloro-2-methyl aniline (0.062 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.059 g of desired product. 1H NMR (DMSO-d6): δ 2.23 (s, 3H), 7.23 (d, J=6.9 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.53 (m, 2H), 7.59 (m, 1H), 7.71 (m, 1H), 8.10 (br s, 4H), 9.98 (br s, 1H), 12.76 (br s, 1H); MS (m/z): 457.18 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:15]=[CH:14][NH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O-]CC.[Na+].CS(O[CH2:25][C@H:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:27])(=O)=O>C(#N)C>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:15]=[CH:14][N:13]([CH2:27][C@H:26]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:25])[N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(-c2cc[nH]n2)ccc(C#N)c1Cl
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(-c2ccn(C[C@@H](C)NC(=O)OC(C)(C)C)n2)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 50.8 %

Procedure:
2-chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.5 g, 2.297 mmol) was dissolved in dry acetonitrile (5 ml) under nitrogen and cooled to 0° C. Sodium ethoxide (0.313 g, 4.59 mmol) was added and the reaction mixture was stirred for 25 min and allowed to warm up to RT. (R)-2-(tert-butoxycarbonylamino)propyl methanesulfonate (0.582 g, 2.297 mmol) was dissolved in 5 ml of dry acetonitrile and added dropwise to the reaction mixture. The reaction mixture was refluxed for 15 h and then the solvents were evaporated. The residue was taken into EtOAc, washed several times with saturated aqueous NaHCO3 and water, dried with Na2SO4 and evaporated to dryness. CombiFlash purification afforded 0.437 g of the title compound using heptane/EtOAc-system as an eluent. 1H-NMR (400 MHz; d6-DMSO): δ 1.02 (d, 3H), 1.31 (s, 9H), 2.57 (s, 3H), 3.91 (m, 1H), 4.13 (m, 2H), 6.62 (m, 1H), 6.87 (d, 1H), 7.66 (d, 1H), 7.78 (d, 1H), 7.83 (d, 1H).