Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11](=O)[C:10]2=O)[CH3:3].[NH2:22][N:23]1[C:27]([NH2:28])=[N:26][N:25]=[C:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>C(O)CO.O>[ClH:1].[CH2:2]([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11]1[C:10]2=[N:22][N:23]2[C:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[N:25][N:26]=[C:27]2[N:28]=1)[CH3:3]
Reactant: CCN(CC)CCc1cc(C)c2c(c1C)C(=O)C(=O)N2
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Agent: Cl
Solvent: OCCO
Solvent: O
Product: CCN(CC)CCc1cc(C)c2[nH]c3nc4nnc(Cc5ccc(O)cc5)n4nc3c2c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.60 mmol of 5-(2-Diethylamino-ethyl)-4,7-dimethyl-1H-indole-2,3-dione hydrochloride (186.5 mg) and 0.70 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (144 mg) in 1.5 mL of ethylene glycol was stirred at 125° C. for 1 day. The mixture was cooled to room temperature, diluted with water (5 mL), stirred for 10 min. Allowed to crystallize in a refrigerator (+5° C.) overnight. The precipitated product was collected by filtration, washed with water (3×1 mL) and dried on high vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([O:28][C:29](=[O:36])[NH:30][C:31]1([CH2:34]I)[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[C:24]([O:28][C:29](=[O:36])[NH:30][C:31]1([CH2:34][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]3[CH:4]=[C:3]([C:15]([NH2:17])=[O:16])[C:2]([NH2:1])=[N:14][C:6]2=3)[CH2:32][CH2:33]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1(CI)CC1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(Cn2c3ccccc3c3cc(C(N)=O)c(N)nc32)CC1
Temperature: 100 °C
Yield: 13 %

Procedure:
To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 318 mg, 1.41 mmol) in N,N-dimethylformamide (17 mL) was added powdered cesium carbonate (2.29 g, 7.03 mmol), tert-butyl[1-(iodomethyl)cyclopropyl]carbamate (2.26 g, 7.61 mmol, prepared from the corresponding alcohol (J. Med. Chem. 1988, 31, 1694-7) following the procedure detailed in the preparation of xxvii below) was added. The mixture was heated at 100° C. under nitrogen for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed thrice with water and twice with brine. The extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (95/5 methylene chloride/methanol to 93/7 methylene chloride/methanol gradient) to afford the titled product (63, 75 mg, 13%). NH4OAc Standard conditions. DAD Retention time =7.29 min. M+H=396; 1H NMR (300 MHz, DMSO-d6): δ 8.72 (s, 1H), 7.79 (d, J=7.3 Hz, 1H), 7.54-7.41 (m, 2H), 7.26 (dd, J=7.3 Hz, 1H), 7.20-7.11 (m, 2H), 4.34 (s, 2H), 1.35 (s, 9H), 1.18-1.05 (m, 2H), 0.65-0.54 (m, 2H).
Reaction SMILES: BrCCCCO[CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH2:15][CH2:16][CH2:7][CH2:8][O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])[CH2:7][CH2:16]2
Reactant: COc1ccccc1S
Reactant: O=C1Nc2ccccc2CC1OCCCCBr
Product: COc1ccccc1SCCCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 2-methoxy-thiophenol.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>CN(C)C=O.O>[CH:47]1([CH2:46][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=34)=[O:20])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=3)=[CH:33][CH:34]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: BrCC1CCCCC1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCC2CCCCC2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and (bromomethyl)cyclohexane (401 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (129 mg, 27%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>>[NH2:32][C:11]1[N:12]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([CH:26]4[CH2:27][CH2:28][N:29]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:31]4)=[CH:20][CH:21]=3)[CH2:16]2)[CH:14]=[C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)[N:10]=1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Product: CC(C)OC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 138 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt and isopropyl chloroformate. LCMS (M+H)+: m/z=508.3.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Product: NS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-aminophenylmethane sulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.1 (d,1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 ( d, 1H), 7.5 (q, 4H), 7.2 (d, 1H), 6.9 (s, 2H), 4.2 (s, 2H); APCI−MS m/z 387 (M+H)+.
Reaction SMILES: Br[CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=[O:8].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[CH:20][C:21]=1[OH:22])=[O:15]>>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:23][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:13]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)CCCCC(C)Br
Product: CC(=O)c1ccc(OC(C)CCCCC(=O)O)cc1O

Procedure:
Following the procedure of Example 40, 4.74 g. of ethyl 6-bromoheptanoate and 3.04 g. of 2,4-dihydroxyacetophenone were reacted in the usual manner and the resulting product hydrolyzed to give the title product, m.p. about 116°-118° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][NH:20][C:21]=2[C:22]#[N:23])=[CH:13][C:12]=1[F:29])=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:30]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:30][N:20]1[C:21]([C:22]#[N:23])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])=[C:12]([F:29])[CH:13]=2)[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19]1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 1-L 3-neck rbf was fitted with an overhead stirrer and charged with sodium hydride (60% dispersion in mineral oil, 2.19 g, 54.6 mmol) and DMF (550 mL). Ethyl 4-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}-5-cyano-1H-pyrrole-3-carboxylate (10.00 g, 45.5 mmol) was added and the mixture was left to stir at rt for 15 min. The reaction mixture was treated with (aminooxy)(diphenyl) phosphine oxide (12.74 g, 54.6 mmol) and heated to 60° C. The very thick reaction mixture gradually became a readily stirred suspension. After 1 h analysis by RP-HPLC indicated that all starting material had been consumed. The reaction was cooled to rt and diluted with 1.5 L EtOAc and aq. sodium bicarbonate. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layers were dried (sodium sulfate) and filtered through a silica plug. Trituration with ether:hexanes (1:2) gave the title compound as a yellowish powder (18.06 g, 46.5 mmol, 93.7%). 1H-NMR (DMSO-d6) 9.13 (s, 1H), 7.68 (s, 1H, 7.68 (t, J=8 Hz, 1H), 7.29 (dd, J=12, 2 Hz, 1H), 7.19 (dd, J=8 Hz, 1H), 6.67 (s, 2H), 4.14 (q, J=7 Hz, 2H), 1.50 (s, 9H), 1.18 (s, 3H); MS [M+Na]+=411.0; LCMS RT=3.48.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH:5]1[CH3:25])#[N:2].[C:26]([CH2:28][C:29](O)=[O:30])#[N:27]>>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:29](=[O:30])[CH2:28][C:26]#[N:27])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH:5]1[CH3:25])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CC1CN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CCC1=CC#N
Product: CC1CN(c2ccc(N3C[C@H](CNC(=O)CC#N)OC3=O)cc2F)CCC1=CC#N
Yield: 81 %

Procedure:
The title compound was prepared as per Example-29 by using (S)-N-{3-[4-(4-cyanomethylidene-3-methylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and cyanoacetic acid in 81% yield.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]=[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]2[C:34]=1[C:35](O)=[O:36]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:34]2[N:28]3[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:27]3=[N:26][C:25]=2[CH3:24])=[O:36])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: Cc1nc2c(C)cccn2c1C(=O)O
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3c(C)cccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,8-Dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:1](=[O:10])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1ccc(C(=O)Nc2ccc3nc(Nc4ncnc5cc(OC)c(OC)cc45)sc3c2)cc1

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)-benzothiazol-6-yl]-4-methoxybenzamide was prepared from p-anisoyl chloride (16 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 46 mg, 94 μmol, 83%). LC/ESI-MS: m/z=488 [M+H]+; m/z=486 [M−H]−; R′, =3.17 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][CH2:2][OH:1])[NH:8][C:7]2=[O:13])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccc(Br)cc1

Procedure:
4-(2-Hydroxyethyl)-1,3-dihydroindol-2-one was condensed with 4-bromobenzaldehyde using method B to give 3-(4-bromobenzylidene)-4-(2-hydroxy-ethyl)-1,3-dihydroindol-2-one as a yellow solid which was reduced using method E to give 0.2 g (91%) of 3-benzyl-4-(2-hydroxyethyl)-1,3-dihydroindol-2-one as a yellow/orange foam.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=1>N1C=CC=CC=1>[CH2:27]([O:26][C:24]([CH2:23][C:21]1[N:22]=[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[S:19][CH:20]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: CCOC(=O)Cc1csc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Reaction time: 48 h
Yield: 62.9 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.1 g) is added to a solution of ethyl (2-aminothiazol-4-yl)acetate (10 g) in pyridine (300 cc). After 48 hours at a temperature of the order of 20° C., the solution is concentrated to dryness under reduced pressure (25 mm Hg; 3.3. kPa) at 60° C. The residue is dissolved in a mixture of methylene chloride (200 cc) and N sodium hydroxide solution (100 cc). The organic phase is decanted off, washed with water (3×100 cc), dried over sodium sulphate and then concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. The residue is recrystallised by dissolving it in boiling acetonitrile (100 cc) and then cooling. The crystals formed are filtered off, washed with acetonitrile (20 cc) and then with diethyl ether (20 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(4-ethoxycarbonylmethylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (11.7 g), m.p.=105° C.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[C:27][C:2]3[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=3)=[N:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: CC(O)COc1ccc(I)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CC(O)COc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared according to general working method I from 1-(4-iodo-phenoxy)-propan-2-ol (2.00 g, 7.19 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (1.54 g, 7.20 mmol).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:48]([O:52][C:53](=[O:62])[NH:54][CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][NH:57]1)([CH3:51])([CH3:50])[CH3:49]>C(#N)C>[C:48]([O:52][C:53](=[O:62])[NH:54][CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][N:57]1[C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Reactant: O=C(O)c1nc(Br)sc1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1C(=O)c1nc(Br)sc1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
2-bromo-5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid (1.02 g, 3.38 mmol) was dissolved in acetonitrile (20 ml) followed by the addition of TBTU (1.19 g, 3.72 mmol) and DIPEA (547 mg, 4.22 mmol). Stirring was continued for 30 min. at rt. A solution of (S)-piperidin-2-ylmethyl-carbamic acid tert-butyl ester (725 mg, 3.38 mmol) in acetonitrile (20 ml) was added to the reaction mixture within 10 minutes and stiring was continued at rt for 24 h. The reaction mixture was concentrated under reduced pressure followed by the addition of aq. HCl (0.5 M, 50 ml). Stirring was continued for 30 min. The precipitated product was filtered off, washed with cold water and dried at HV to give the expected product (1.57 g). LC-MS: tR=1.03 min; [M+H]+=500.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[C:30]1[S:31][C:32]2[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:33]=2[N:34]=1)[NH2:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:4]=1[C:5]([NH:26][C:25]1[CH:27]=[CH:28][C:29]([C:30]2[S:31][C:32]3[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:23]([O:22][CH3:21])[CH:24]=1)=[O:7]
Reactant: COc1ccc2nc(-c3ccc(N)cc3OC)sc2c1
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(-c3ccc(NC(=O)c4cc(OC(F)(F)F)ccc4OC)cc3OC)sc2c1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A stirred mixture of 2-methoxy-5-trifluoromethoxybenzoic acid (0.248 g, 1.05 mmol) and thionyl chloride (4 ml) was heated under reflux for 4 h. After cooling to room temperature, the excess reagent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride and 3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)aniline (0.30 g, 1.05 mmol) in dry pyridine (8 ml) to give the title compound (0.389 g, 73%) as an almost colourless solid after work-up and recrystallisation from acetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](=[O:21])[NH:35][CH2:36][C:37](=[O:38])[N:39]([CH3:41])[CH3:40])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1)[CH3:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)CN
Reactant: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CCN(C)C(=O)OC(C)(C)C
Yield: 41.1 %

Procedure:
{2-[2-(6-Chloro-benzothiazol-2-ylamino)-5-(dimethylcarbamoylmethyl-carbamoyl)-benzoimidazol-1-yl]ethyl}-methyl-carbamic acid tert-butyl ester (70 mg) was prepared by following General Procedure F starting from 1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (146 mg), 2-amino-N,N-dimethyl-acetamide (50 mg), HBTU (125 mg), and DIEA (100 uL) in DMF (1 mL).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]2)=[CH:7][C:5]=1[NH2:6])([O-])=O.O.Cl>[Fe].C(O)C>[O:17]=[C:14]1[CH:15]=[CH:16][N:11]([C:8]2[CH:9]=[CH:10][C:4]([NH2:1])=[C:5]([NH2:6])[CH:7]=2)[CH:12]=[CH:13]1
Reactant: Nc1cc(-n2ccc(=O)cc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-n2ccc(=O)cc2)cc1N
Yield: 86.2 %

Procedure:
First, 5.515 g of 2-nitro-5-(4-oxo-4H-pyridin-1-yl)-aniline was added to a suspension containing 7.975 g of iron powder, 20 ml of water, and 78 ml of ethanol, followed by adding 2 ml of 2N hydrochloric acid. The resultant mixture was refluxed by heating for 6 hours. Then, 1.092 g of iron powder and 2 ml of 2N hydrochloric acid were added to the mixture. The resultant mixture was refluxed for another 1 hour. After the reaction, the reaction mixture was hot filtered using celite, and a residue on the celite was thoroughly washed with warm ethanol. The mother liquor and the washings were combined together and concentrated to dryness. The residue thus obtained was subjected to silica gel column chromatography, and fractions eluted with 5% methanol in chloroform were collected. The collected fractions were combined and evaporated. The residue was recrystallized with isopropanol-methanol (1:1) to give 4.137 g of orange crystals of 4-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine.
Reaction SMILES: CO[CH:3](OC)[CH2:4]C(OC)OC.[CH:12]1([NH:17][NH:18][C:19](OC(C)(C)C)=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O>[CH:12]1([N:17]2[CH:4]=[CH:3][CH:19]=[N:18]2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NNC1CCCC1
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: O
Product: c1cnn(C2CCCC2)c1
Yield: 71 %

Procedure:
A mixture of 1,1,3,3-tetramethoxypropane (13.6 g, 83 mmol) and N2-cyclopentyl-N1-(tert-butoxycarbonyl)hydrazine (16.6 g, 83 mmol, see Ranatunge et al., J. Med. Chem. (2004), 47, p2180-2193) in water (150 mL) was treated with cone. HCl (21 mL, 252 mmol). The resulting mixture was heated at reflux overnight. The completed reaction mixture was extracted with ether and the extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give 1-cyclopentyl-1 H-pyrazole (8.0 g, 71% yield. 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 1 H), 7.43 (s, 1 H), 6.24 (s, 1 H), 4.68 (m, 1 H), 2.20-1.71 (m, 8 H). MS (ESI) m/z; 137.1 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1>>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)nc1
Product: Cn1cc(-c2cc(Oc3ccc(N)cn3)ccn2)cn1
Yield: 64 %

Procedure:
Using a procedure analogous to Example A13, 6-(2-chloropyridin-4-yloxy)pyridin-3-amine (6.06 g, 27.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.53 g, 41.0 mmol) were combined to provide 6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-3-amine (4.67 g, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.3 (m, 1H), 8.2 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.3 (s, 1H), 7.25-7.2 (m, 1H), 6.85-6.81 (m, 1H), 6.6-6.55 (m, 1H), 5.3 (s, 2H), 3.8 (s, 3H); MS (ESI) m/z: 268.1 (M+H+).